curcumin and Breast-Neoplasms

Owing to its diverse heterogeneity, aggressive nature, enormous metastatic potential, and high remission rate, the breast cancer (BC) is among the most prevalent types of cancer associated with high mortality. Curcumin (Cur) is a potent phytoconstituent that has gained remarkable recognition due to exceptional biomedical viability against a wide range of ailments including the BC. Despite exhibiting a strong anticancer potential, the clinical translation of Cur is restricted due to intrinsic physicochemical properties such as low aqueous solubility, chemical instability, low bioavailability, and short plasma half-life. To overcome these shortcomings, nanotechnology-aided developments have been extensively deployed. The implication of nanotechnology has pointedly improved the physicochemical properties, pharmacokinetic profile, cell internalization, and anticancer efficacy of Cur; however, majority of Cur-nanomedicines are still facing grandeur challenges. The advent of various functionalization strategies such as PEGylation, surface decoration with different moieties, stimuli-responsiveness (i.e., pH, light, temperature, heat, etc.), tethering of specific targeting ligand(s) based on the biochemical targets (e.g., folic acid receptors, transferrin receptors, CD44, etc.), and multifunctionalization (multiple functionalities) has revolutionized the fate of Cur-nanomedicines. This study ponders the biomedical significance of various Cur-nanomedicines and adaptable functionalizations for amplifying the physicochemical properties, cytotoxicity via induction of apoptosis, cell internalization, bioavailability, passive and active targeting to the tumor microenvironment (TME), and anticancer efficacy of the Cur while reversing the multidrug resistance (MDR) and reoccurrence in BC. Nevertheless, the therapeutic outcomes of Cur-nanomedicines against the BC have been remarkably improved after adaptation of various functionalizations; however, this evolving strategy still demands extensive research for scalable clinical translation.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Curcumin; Female; Humans; Nanomedicine; Nanoparticles; Nanotechnology; Tumor Microenvironment

Radiation dermatitis (RD) is a common side effect of radiotherapy in most breast cancer patients. Curcumin has recently attracted more attention for managing the side effects of breast cancer treatments. This review study aimed to investigate the effect of curcumin on the severity of radiation dermatitis in patients with breast cancer.   Methods: All eligible randomized controlled trials (RCTs) were collected by searching PubMed, Scopus, Cochrane, and Web of Science. The effect size was expressed as weighted mean difference (WMD) and 95% confidence interval (CI). Study heterogeneity was assessed through Q statistics and I-squared.. Four RCTs with 882 patients were included in the final analysis. The results of the meta-analysis indicated that curcumin supplementation significantly reduced radiation dermatitis severity (RDS) score in the intervention group compared to the control group (WMD=-0.50; 95% CI -0.72 to -0.27, P <0.001). A significant heterogeneity was observed between the studies (I2 = 95.7%, P < 0.001).. Based on the results of the present study, curcumin has significant effects in reducing the severity of radiation dermatitis in breast cancer patients receiving radiotherapy. Further well-designed longitudinal studies are recommended to confirm these results and to discover the underlying mechanisms of the effects of curcumin on the severity of radiation dermatitis in patients with cancer.

Topics: Breast Neoplasms; Curcumin; Dietary Supplements; Female; Humans; Radiodermatitis; Randomized Controlled Trials as Topic

Breast cancer (BC) is the most prevalent type of cancer in the world and the main reason women die from cancer. Due to the significant side effects of conventional treatments such as chemotherapy and radiotherapy, the search for supplemental and alternative natural drugs with lower toxicity and side effects is of interest to researchers. Curcumin (CUR) is a natural polyphenol extracted from turmeric. Numerous studies have demonstrated that CUR is an effective anticancer drug that works by modifying different intracellular signaling pathways. CUR's therapeutic utility is severely constrained by its short half-life in vivo, low water solubility, poor stability, quick metabolism, low oral bioavailability, and potential for gastrointestinal discomfort with high oral doses. One of the most practical solutions to the aforementioned issues is the development of targeted drug delivery systems (TDDSs) based on nanomaterials. To improve drug targeting and efficacy and to serve as a reference for the development and use of CUR TDDSs in the clinical setting, this review describes the physicochemical properties and bioavailability of CUR and its mechanism of action on BC, with emphasis on recent studies on TDDSs for BC in combination with CUR, including passive TDDSs, active TDDSs and physicochemical TDDSs.

Topics: Antineoplastic Agents; Breast Neoplasms; Curcumin; Drug Carriers; Drug Delivery Systems; Female; Humans; Solubility

Breast cancer is the most prevalent cancer worldwide, with high morbidity and mortality. Despite great advances in the therapeutic strategies, the survival rate in the past decades of patients with breast cancer remains unsatisfactory. Growing evidence has demonstrated that Curcumae Rhizoma, called Ezhu in Chinese, showed various pharmacological properties, including anti-bacterial, anti-oxidant, anti-inflammatory and anti-tumor activities. It has been widely used in Chinese medicine to treat many types of human cancer.. To comprehensively summarize and analyze the effects of active substances in Curcumae Rhizoma on breast cancer malignant phenotypes and the underlying mechanisms, as well as discuss its medicinal value and future perspectives.. We used "Curcumae Rhizoma" or the name of crude extracts and bioactive components in Curcumae Rhizoma in combination with "breast cancer" as key words. Studies focusing on their anti-breast cancer activities and mechanisms of action were extracted from Pubmed, Web of Science and CNKI databases up to October 2022. The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 guideline was followed.. Crude extracts and 7 main bioactive phytochemicals (curcumol, β-elemene, furanodiene, furanodienone, germacrone, curdione and curcumin) isolated from Curcumae Rhizoma have shown many anti-breast cancer pharmacological properties, including inhibiting cell proliferation, migration, invasion and stemness, reversing chemoresistance, and inducing cell apoptosis, cycle arrest and ferroptosis. The mechanisms of action were involved in regulating MAPK, PI3K/AKT and NF-κB signaling pathways. In vivo and clinical studies demonstrated that these compounds exhibited high anti-tumor efficacy and safety against breast cancer.. These findings provide strong evidence that Curcumae Rhizoma acts as a rich source of phytochemicals and has robust anti-breast cancer properties.

Topics: Breast Neoplasms; Curcuma; Drugs, Chinese Herbal; Female; Humans; Phosphatidylinositol 3-Kinases; Rhizome; Signal Transduction

The primary source of failure of cancer therapies is multidrug resistance (MDR), which can be caused by different mechanisms, including the overexpression of ABC transporters in cancer cells. Among the 48 human ABC proteins, the breast cancer resistance protein (BCRP/ABCG2) has been described as a pivotal player in cancer resistance. The use of functional inhibitors and expression modulators is a promising strategy to overcome the MDR caused by ABCG2. Despite the lack of clinical trials using ABCG2 inhibitors, many compounds have already been discovered. This review presents an overview about various ABCG2 inhibitors that have been identified, discussing some chemical aspects and the main experimental methods used to identify and characterize the mechanisms of new inhibitors. In addition, some biological requirements to pursue preclinical tests are described. Finally, we discuss the potential use of ABCG2 inhibitors in cancer stem cells (CSC) for improving the objective response rate and the mechanism of ABCG2 modulators at transcriptional and protein expression levels.

Topics: Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily G, Member 2; Breast Neoplasms; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Humans; Neoplasm Proteins; Neoplastic Stem Cells

Female breast cancer is the world's most prevalent cancer in 2020. Chemotherapy still remains a backbone in breast cancer therapy and is crucial in advanced and metastatic breast cancer treatment. The clinical efficiency of chemotherapy regimens is limited due to tumor heterogeneity, chemoresistance, and side effects. Chemotherapeutic drug combinations with natural products hold great promise for enhancing their anticancer efficacy. Curcumin is an ideal chemopreventive and chemotherapy agent owning to its multitargeting function on various regulatory molecules, key signaling pathways, and pharmacological safety. This review aimed to elucidate the potential role of curcumin in enhancing the efficacy of doxorubicin, paclitaxel, 5-fluorouracil, and cisplatin via combinational therapy. Additionally, the molecular mechanisms underlying the chemosensitizing activity of these combinations have been addressed. Overall, based on the promising therapeutic potential of curcumin in combination with conventional chemotherapy drugs, curcumin is of considerable value to develop as an adjunct for combination chemotherapy with current drugs to treat breast cancer. Furthermore, this topic may provide the frameworks for the future research direction of curcumin-chemotherapy combination studies and may benefit in the development of a novel therapeutic strategy to maximize the clinical efficacy of anticancer drugs while minimizing their side effects in the future breast cancer treatment.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Curcumin; Humans; Signal Transduction

Curcumin is a potential plant-derived drug for the treatment of breast cancer. Poor solubility and bioavailability are the main factors that limit its clinical application. Various structural modification strategies have been developed to improve the anti-breast cancer activity of curcumin. This review focuses on the difference of modification sites and heterocyclic/non-heterocyclic modifications to systematically summarize curcumin derivatives with better anti-breast cancer activity.

Topics: Antineoplastic Agents; Biological Availability; Breast Neoplasms; Curcumin; Female; Humans; Solubility

Polyphenols represent a structural class of mainly natural organic chemicals that contain multiple phenol structural units. The beneficial properties of polyphenols have been extensively studied for their antitumor, anti-inflammatory, and antibacterial effects, but nowadays, their medical applications are starting to be extended to many other applications due to their prebiotic role and their impact on the microbiota. This review focused on the use of polyphenols in cancer treatment. Their antineoplastic effects have been demonstrated in various studies when they were tested on numerous cancer lines and some in in vivo models. A431 and SCC13 human skin cancer cell lines treated with EGCG presented a reduced cell viability and enhanced cell death due to the inactivation of β-catenin signaling. Additionally, resveratrol showed a great potential against breast cancer mainly due to its ability to exert both anti-estrogenic and estrogenic effects (based on the concentration) and because it has a high affinity for estrogen receptors ERα and Erβ. Polyphenols can be combined with different classical cytostatic agents to enhance their therapeutic effects on cancer cells and to also protect healthy cells from the aggressiveness of antitumor drugs due to their anti-inflammatory properties. For instance, curcumin has been reported to reduce the gastrointestinal toxicity associated with chemotherapy. In the case of 5-FU-induced, it reduced the gastrointestinal toxicity by increasing the intestinal permeability and inhibiting mucosal damage. Co-administration of EGCG and doxorubicin induced the death of liver cancer cells. EGCG has the ability to inhibit autophagic activity and stop hepatoma Hep3B cell proliferation This symbiotic approach is well-known in medical practice including in multiple chemotherapy.

Topics: Anti-Bacterial Agents; Antineoplastic Agents; beta Catenin; Breast Neoplasms; Catechin; Curcumin; Cytostatic Agents; Doxorubicin; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogens; Female; Fluorouracil; Humans; Liver Neoplasms; Polyphenols; Receptors, Estrogen; Resveratrol

Breast cancer (BC), the most common malignancy in women, results from significant alterations in genetic and epigenetic mechanisms that alter multiple signaling pathways in growth and malignant progression, leading to limited long-term survival. Current studies with numerous drug therapies have shown that BC is a complex disease with tumor heterogeneity, rapidity, and dynamics of the tumor microenvironment that result in resistance to existing therapy. Targeting a single cell-signaling pathway is unlikely to treat or prevent BC. Curcumin (a natural yellow pigment), the principal ingredient in the spice turmeric, is well-documented for its diverse pharmacological properties including anti-cancer activity. However, its clinical application has been limited because of its low solubility, stability, and bioavailability. To overcome the limitation of curcumin, several modified curcumin conjugates and curcumin mimics were developed and studied for their anti-cancer properties. In this review, we have focused on the application of curcumin mimics and their conjugates for breast cancer.

Topics: Antineoplastic Agents; Breast Neoplasms; Curcumin; Female; Humans; Signal Transduction; Solubility; Tumor Microenvironment

Unprecedented community containment measures were taken following the recent outbreak of COVID-19 in Italy. The aim of the study was to explore the self-reported future compliance of citizens with such measures and its relationship with potentially impactful psychological variables.. An online survey was completed by 931 people (18-76 years) distributed across the Italian territory. In addition to demographics, five dimensions were measured: self-reported compliance with containment measures over time (today, at 7, 14, 30, 60, 90, and 180 days from now) at three hypothetical risk levels (10, 50, 90% of likelihood of contracting the COVID-19), perceived risk, generalized anxiety, intolerance of uncertainty, and relevance of several psychological needs whose satisfaction is currently precluded.. The duration of containment measures plays a crucial role in tackling the spread of the disease as people will be less compliant over time. Psychological needs of citizens impacting on the compliance should be taken into account when planning an easing of the lockdown, along with interventions for protecting vulnerable groups from mental distress.. La apendicitis aguda (AA) es la urgencia quirúrgica abdominal más frecuente. No encontramos estudios específicos que evalúen el impacto de la pandemia causada por el coronavirus 2 (SARS-Cov-2) sobre la AA y su tratamiento quirúrgico. Analizamos la influencia de esta nueva patología sobre la AA.. Estudio observacional retrospectivo en pacientes intervenidos por AA desde enero hasta abril de 2020. Fueron clasificados según el momento de la apendicectomía, antes de la declaración del estado de alarma (Pre-COVID19) y después de la declaración del estado de alarma (Post-COVID19) en España. Se evaluaron variables demográficas, duración de la sintomatología, tipo de apendicitis, tiempo quirúrgico, estancia hospitalaria y complicaciones postoperatorias.. La pandemia por SARS-Cov-2 influye en el momento de diagnóstico de la apendicitis, así como en su grado de evolución y estancia hospitalaria. La peritonitis fue lo más frecuentemente observado. Una sospecha y orientación clínica más temprana, es necesaria para evitar un manejo inadecuado de este trastorno quirúrgico común.. The primary outcome is improvement in PaO. Findings will provide timely information on the safety, efficacy, and optimal dosing of t-PA to treat moderate/severe COVID-19-induced ARDS, which can be rapidly adapted to a phase III trial (NCT04357730; FDA IND 149634).. None.. The gut barrier is crucial in cirrhosis in preventing infection-causing bacteria that normally live in the gut from accessing the liver and other organs via the bloodstream. Herein, we characterised gut inflammation by measuring different markers in stool samples from patients at different stages of cirrhosis and comparing this to healthy people. These markers, when compared with equivalent markers usually measured in blood, were found to be very different in pattern and absolute levels, suggesting that there is significant gut inflammation in cirrhosis related to different immune system pathways to that seen outside of the gut. This provides new insights into gut-specific immune disturbances that predispose to complications of cirrhosis, and emphasises that a better understanding of the gut-liver axis is necessary to develop better targeted therapies.. La surveillance de l’intervalle QT a suscité beaucoup d’intérêt durant la pandémie de la COVID-19 en raison de l’utilisation de médicaments prolongeant l’intervalle QT et les préoccupations quant à la transmission virale par les électrocardiogrammes (ECG) en série. Nous avons posé l’hypothèse que la surveillance en continu de l’intervalle QT par télémétrie était associée à une meilleure détection des épisodes de prolongation de l’intervalle QT.. Nous avons introduit la télémétrie cardiaque en continu (TCC) à l’aide d’un algorithme de surveillance automatisée de l’intervalle QT dans nos unités de COVID-19. Les mesures automatisées quotidiennes de l’intervalle QT corrigé (auto-QTc) en fonction de la fréquence cardiaque maximale ont été enregistrées. Nous avons comparé la proportion des épisodes de prolongation marquée de l’intervalle QTc (QTc long), définie par un intervalle QTc ≥ 500 ms, chez les patients montrant une suspicion de COVID-19 ou ayant la COVID-19 qui avaient été admis avant et après la mise en place de la TCC (groupe témoin. La surveillance en continu de l’intervalle QT est supérieure à la norme de soins dans la détection des épisodes de QTc long et exige peu d’ECG. La réponse clinique aux épisodes de QTc long est sous-optimale.. Exposure to a model wildfire air pollution source modifies cardiovascular responses to HC challenge, suggesting air pollution sensitizes the body to systemic triggers.. Though the majority of HIV-infected adults who were on HAART had shown viral suppression, the rate of suppression was sub-optimal according to the UNAIDS 90-90-90 target to help end the AIDS pandemic by 2020. Nonetheless, the rate of immunological recovery in the study cohort was low. Hence, early initiation of HAART should be strengthened to achieve good virological suppression and immunological recovery.. Dust in Egyptian laying hen houses contains high concentrations of microorganisms and endotoxins, which might impair the health of birds and farmers when inhaled. Furthermore, laying hens in Egypt seem to be a reservoir for ESBL-producing Enterobacteriaceae. Thus, farmers are at risk of exposure to ESBL-producing bacteria, and colonized hens might transmit these bacteria into the food chain.. The lack of significant differences in the absolute changes and relative ratios of injury and repair biomarkers by contrast-associated AKI status suggests that the majority of mild contrast-associated AKI cases may be driven by hemodynamic changes at the kidney.. Most comparisons for different outcomes are based on very few studies, mostly low-powered, with an overall low CoE. Thus, the available evidence is considered insufficient to either support or refute CH effectiveness or to recommend one ICM over another. Therefore, further well-designed, larger RCTs are required.. PROSPERO database Identifier: CRD42016041953.. Untouched root canal at cross-section perimeter, the Hero 642 system showed 41.44% ± 5.62% and Reciproc R40 58.67% ± 12.39% without contact with instruments. Regarding the untouched area, Hero 642 system showed 22.78% ± 6.42% and Reciproc R40 34.35% ± 8.52%. Neither instrument achieved complete cross-sectional root canal debridement. Hero 642 system rotary taper 0.02 instruments achieved significant greater wall contact perimeter and area compared to reciprocate the Reciproc R40 taper 0.06 instrument.. Hero 642 achieved higher wall contact perimeter and area but, regardless of instrument size and taper, vital pulp during. The functional properties of the main mechanisms involved in the control of muscle Ca. This study showed that the anti-inflammatory effect of the iron-responsive product DHA in arthritis can be monitored by an iron-like radioactive tracer (. Attenuated vascular reactivity during pregnancy suggests that the systemic vasodilatory state partially depletes nitric oxide bioavailability. Preliminary data support the potential for MRI to identify vascular dysfunction in vivo that underlies PE. Level of Evidence 2 Technical Efficacy Stage 1 J. MAGN. RESON. IMAGING 2021;53:447-455.. La evaluación de riesgo es importante para predecir los resultados postoperatorios en pacientes con cáncer gastroesofágico. Este estudio de cohortes tuvo como objetivo evaluar los cambios en la composición corporal durante la quimioterapia neoadyuvante e investigar su asociación con complicaciones postoperatorias. MÉTODOS: Los pacientes consecutivos con cáncer gastroesofágico sometidos a quimioterapia neoadyuvante y cirugía con intención curativa entre 2016 y 2019, identificados a partir de una base de datos específica, se incluyeron en el estudio. Se utilizaron las imágenes de tomografía computarizada, antes y después de la quimioterapia neoadyuvante, para evaluar el índice de masa muscular esquelética, la sarcopenia y el índice de grasa visceral y subcutánea.. In this in vitro premature infant lung model, HF oscillation of BCPAP was associated with improved CO. Our results showed that HPC significantly promotes neurogenesis after MCAO and ameliorates neuronal injury.. Inflammatory markers are highly related to signs of systemic hypoperfusion in CS. Moreover, high PCT and IL-6 levels are associated with poor prognosis.. These findings indicate that Tetrapleura tetraptera fruit has a protective potential against stroke through modulation of redox and electrolyte imbalances, and attenuation of neurotransmitter dysregulation and other neurochemical dysfunctions. Tetrapleura tetraptera fruit could be a promising source for the discovery of bioactives for stroke therapy.

Topics: 3T3-L1 Cells; A Kinase Anchor Proteins; Acetates; Achilles Tendon; Acute Kidney Injury; Acute Pain; Acyclic Monoterpenes; Adenine Nucleotides; Adhesins, Escherichia coli; Adipocytes; Adipocytes, Brown; Adipogenesis; Administration, Inhalation; Administration, Oral; Adrenal Cortex Hormones; Adsorption; Adult; Aeromonas hydrophila; Africa; Aged; Aged, 80 and over; Agrobacterium tumefaciens; Air; Air Pollutants; Air Pollution; Air Pollution, Indoor; Algorithms; Alkaloids; Alkynes; Allosteric Regulation; Amines; Amino Acid Sequence; Amino Acids; Amino Acids, Branched-Chain; Aminoisobutyric Acids; Aminopyridines; Amyotrophic Lateral Sclerosis; Anaerobic Threshold; Angiography; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animal Distribution; Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Ankle Joint; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Inflammatory Agents; Antibodies, Bacterial; Antifungal Agents; Antimalarials; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antioxidants; Antiretroviral Therapy, Highly Active; Antiviral Agents; Aotidae; Apelin; Apoptosis; Arabidopsis Proteins; Argentina; Arginine; Artemisinins; Arthritis, Experimental; Arthritis, Rheumatoid; Arthroscopy; Aspergillus; Aspergillus niger; Asteraceae; Asthma; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; Auditory Cortex; Autoantibodies; Autophagy; Bacteria; Bacterial Infections; Bacterial Proteins; Bacterial Typing Techniques; Base Composition; Base Sequence; Basketball; Beclin-1; Benzhydryl Compounds; Benzimidazoles; Benzo(a)pyrene; Benzofurans; Benzoxazines; Bereavement; beta Catenin; beta-Lactamase Inhibitors; beta-Lactamases; beta-Lactams; Betacoronavirus; Betaine; Binding Sites; Biofilms; Biological Assay; Biological Availability; Biological Evolution; Biomarkers; Biomechanical Phenomena; Biopolymers; Biopsy; Bismuth; Blood Glucose; Blood Platelets; Blood Pressure; Body Composition; Body Weight; Bone Marrow; Bone Marrow Cells; Bone Regeneration; Boron; Botrytis; Brain Ischemia; Brain Neoplasms; Brain-Derived Neurotrophic Factor; Brazil; Breast Neoplasms; Breath Tests; Bronchoalveolar Lavage Fluid; Burkholderia; C-Reactive Protein; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Calcification, Physiologic; Calcium; Calcium Signaling; Calorimetry, Differential Scanning; Cameroon; Camptothecin; Candida; Candida albicans; Capillaries; Carbapenem-Resistant Enterobacteriaceae; Carbapenems; Carbohydrate Conformation; Carbon; Carbon Dioxide; Carbon Isotopes; Carcinoma, Ovarian Epithelial; Cardiac Output; Cardiomyopathy, Hypertrophic; Cardiotonic Agents; Cardiovascular Diseases; Caregivers; Carps; Case-Control Studies; Catalase; Catalysis; Cats; CD4 Lymphocyte Count; Cell Culture Techniques; Cell Differentiation; Cell Line, Tumor; Cell Membrane; Cell Movement; Cell Proliferation; Cell Survival; Cells, Cultured; Cellulose; Centrosome; Ceratopogonidae; Chickens; Child; China; Cholera Toxin; Choline; Cholinesterases; Chromatography, High Pressure Liquid; Chromatography, Liquid; Chromatography, Micellar Electrokinetic Capillary; Chromatography, Reverse-Phase; Chronic Disease; Cinnamates; Cities; Citrates; Climate Change; Clinical Trials, Phase III as Topic; Coal; Coal Mining; Cohort Studies; Coinfection; Colchicine; Colony Count, Microbial; Colorectal Neoplasms; Coloring Agents; Common Cold; Complement Factor H; Computational Biology; Computer Simulation; Continuous Positive Airway Pressure; Contrast Media; Coordination Complexes; Coronary Artery Bypass; Coronavirus 3C Proteases; Coronavirus Infections; Coronavirus Protease Inhibitors; Corynebacterium glutamicum; Cosmetics; COVID-19; Creatinine; Cross-Sectional Studies; Crotonates; Crystallography, X-Ray; Cues; Culicidae; Culture Media; Curcuma; Cyclopentanes; Cyclopropanes; Cymbopogon; Cystine; Cytochrome P-450 CYP2B6; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2C19 Inhibitors; Cytokines; Databases, Genetic; Death; Dendritic Cells; Density Functional Theory; Depsides; Diabetes Mellitus, Type 2; Diamond; Diarylheptanoids; Dibenzofurans; Dibenzofurans, Polychlorinated; Diclofenac; Diet; Dietary Carbohydrates; Dietary Supplements; Diffusion Magnetic Resonance Imaging; Dioxins; Diphenylamine; Disease Outbreaks; Disease Susceptibility; Disulfides; Dithiothreitol; Dizocilpine Maleate; DNA Methylation; DNA-Binding Proteins; DNA, Bacterial; Dogs; Dose-Response Relationship, Drug; Double-Blind Method; Doublecortin Protein; Drosophila melanogaster; Droughts; Drug Carriers; Drug Combinations; Drug Delivery Systems; Drug Liberation; Drug Resistance; Drug Resistance, Bacterial; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Dust; Dynactin Complex; Dysferlin; Echo-Planar Imaging; Echocardiography; Edaravone; Egypt; Elasticity; Electrodes; Electrolytes; Emodin; Emtricitabine; Endometriosis; Endothelium, Vascular; Endotoxins; Energy Metabolism; Energy Transfer; Enterobacteriaceae; Enterococcus faecalis; Enterotoxigenic Escherichia coli; Environmental Monitoring; Enzyme Inhibitors; Epidemiologic Factors; Epigenesis, Genetic; Erythrocytes; Escherichia coli; Escherichia coli Infections; Escherichia coli Vaccines; Esophageal Neoplasms; Esophagectomy; Esophagogastric Junction; Esterases; Esterification; Ethanol; Ethiopia; Ethnicity; Eucalyptus; Evidence-Based Practice; Exercise; Exercise Tolerance; Extracorporeal Membrane Oxygenation; Family; Fatty Acids; Feedback; Female; Ferric Compounds; Fibrin Fibrinogen Degradation Products; Filtration; Fish Diseases; Flavonoids; Flavonols; Fluorodeoxyglucose F18; Follow-Up Studies; Food Microbiology; Food Preservation; Forests; Fossils; Free Radical Scavengers; Freund's Adjuvant; Fruit; Fungi; Gallium; Gender Identity; Gene Expression Regulation; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Plant; Gene Knockdown Techniques; Genes, Bacterial; Genes, Plant; Genetic Predisposition to Disease; Genitalia; Genotype; Glomerulonephritis, IGA; Glottis; Glucocorticoids; Glucose; Glucuronides; Glutathione Transferase; Glycogen Synthase Kinase 3 beta; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Grassland; Guinea Pigs; Half-Life; Head Kidney; Heart Atria; Heart Rate; Heart Septum; HEK293 Cells; Hematopoietic Stem Cells; Hemodynamics; Hep G2 Cells; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Hepatocytes; Hesperidin; High-Frequency Ventilation; High-Temperature Requirement A Serine Peptidase 1; Hippocampus; Hirudins; History, 20th Century; History, 21st Century; HIV Infections; Homeostasis; Hominidae; Housing, Animal; Humans; Hydrocarbons, Brominated; Hydrogen Bonding; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydroxybutyrates; Hydroxyl Radical; Hypertension; Hypothyroidism; Image Interpretation, Computer-Assisted; Immunoconjugates; Immunogenic Cell Death; Indoles; Infant, Newborn; Infant, Premature; Infarction, Middle Cerebral Artery; Inflammation; Inflammation Mediators; Infrared Rays; Inhibitory Concentration 50; Injections, Intravenous; Interferon-gamma; Interleukin-23; Interleukin-4; Interleukin-6; Intermediate Filaments; Intermittent Claudication; Intestine, Small; Iridoid Glucosides; Iridoids; Iron; Isomerism; Isotope Labeling; Isoxazoles; Itraconazole; Kelch-Like ECH-Associated Protein 1; Ketoprofen; Kidney Failure, Chronic; Kinetics; Klebsiella pneumoniae; Lactams, Macrocyclic; Lactobacillus; Lactulose; Lakes; Lamivudine; Laparoscopy; Laparotomy; Laryngoscopy; Leucine; Limit of Detection; Linear Models; Lipid A; Lipopolysaccharides; Listeria monocytogenes; Liver; Liver Cirrhosis; Logistic Models; Longitudinal Studies; Losartan; Low Back Pain; Lung; Lupinus; Lupus Erythematosus, Systemic; Machine Learning; Macular Degeneration; Madin Darby Canine Kidney Cells; Magnetic Phenomena; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Magnetics; Malaria, Falciparum; Male; Mannans; MAP Kinase Signaling System; Mass Spectrometry; Melatonin; Membrane Glycoproteins; Membrane Proteins; Meniscectomy; Menisci, Tibial; Mephenytoin; Mesenchymal Stem Cells; Metal Nanoparticles; Metal-Organic Frameworks; Methionine; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Nude; Mice, Obese; Mice, Transgenic; Microbial Sensitivity Tests; Microcirculation; MicroRNAs; Microscopy, Video; Microtubules; Microvascular Density; Microwaves; Middle Aged; Minimally Invasive Surgical Procedures; Models, Animal; Models, Biological; Models, Molecular; Models, Theoretical; Molecular Docking Simulation; Molecular Structure; Molecular Weight; Morus; Mouth Floor; Multicenter Studies as Topic; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Muscle, Skeletal; Myocardial Ischemia; Myocardium; NAD; NADP; Nanocomposites; Nanoparticles; Naphthols; Nasal Lavage Fluid; Nasal Mucosa; Neisseria meningitidis; Neoadjuvant Therapy; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Neoplasms, Experimental; Neural Stem Cells; Neuroblastoma; Neurofilament Proteins; 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Plant Oils; Plants, Medicinal; Plasmodium berghei; Plasmodium falciparum; Platelet Activation; Platelet Function Tests; Pneumonia, Viral; Poaceae; Pogostemon; Poloxamer; Poly I; Poly(ADP-ribose) Polymerase Inhibitors; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Polycyclic Compounds; Polyethylene Glycols; Polylysine; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Population Dynamics; Portasystemic Shunt, Transjugular Intrahepatic; Positron Emission Tomography Computed Tomography; Postoperative Complications; Postprandial Period; Potassium Cyanide; Predictive Value of Tests; Prefrontal Cortex; Pregnancy; Prepulse Inhibition; Prevalence; Procalcitonin; Prodrugs; Prognosis; Progression-Free Survival; Proline; Proof of Concept Study; Prospective Studies; Protein Binding; Protein Conformation; Protein Domains; Protein Folding; Protein Multimerization; Protein Sorting Signals; Protein Structure, Secondary; Proton Pump Inhibitors; Protozoan Proteins; Psychometrics; Pulse Wave Analysis; 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Tissue Distribution; Titanium; Toluidines; Tomography, X-Ray Computed; Tooth; Tramadol; Transcription Factor AP-1; Transcription, Genetic; Transfection; Transgender Persons; Translations; Treatment Outcome; Triglycerides; Ubiquinone; Ubiquitin-Specific Proteases; United Kingdom; United States; Up-Regulation; Vascular Stiffness; Veins; Ventricular Remodeling; Viral Load; Virulence Factors; Virus Replication; Vitis; Voice; Voice Quality; Wastewater; Water; Water Pollutants, Chemical; Water-Electrolyte Balance; Weather; Wildfires; Wnt Signaling Pathway; Wound Healing; X-Ray Diffraction; Xenograft Model Antitumor Assays; Young Adult; Zoogloea

Breast cancer is the second most leading cause of death among women. Multiple drugs have been approved by FDA for the treatment of BC. The major drawbacks of existing drugs are the development of resistance, toxicity, selectivity problem. The other therapies like hormonal therapy, surgery, radiotherapy, and immune therapy are in use but showed many side effects like bioavailability issues, non-selectivity, pharmacokinetic-pharmacodynamic problems. Therefore, there is an urgent need to develop new moieties that are nonviolent and more effective in the treatment of cancer. Isoxazole derivatives have gain popularity in recent years due to anticancer potential with the least side effects. These derivatives act as an anticancer agent with different mechanisms like inducing apoptosis, aromatase inhibition, disturbing tubulin congregation, topoisomerase inhibition, HDAC inhibition, and ERα inhibition. In this article, we have explored the synthetic strategies, anticancer mechanism of action along with SAR studies of isoxazole derivatives.

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Proliferation; Drug Screening Assays, Antitumor; Female; Humans; Isoxazoles

One of the most systematically studied bioactive nutraceuticals for its benefits in the management of various diseases is the turmeric-derived compounds: curcumin. Turmeric obtained from the rhizome of a perennial herb

Topics: Breast Neoplasms; Curcuma; Curcumin; DNA Methylation; Epigenomics; Female; Gene Expression Regulation, Neoplastic; Humans; Rhizome

Cancer is hyper-proliferative, multi-factorial and multi-step, heterogeneous group of molecular disorders. It is the second most reported disease after heart diseases. Breast carcinoma is the foremost death causing disease in female population worldwide. Cancer can be controlled by regulating the gene expression. Current therapeutic options are associated with severe side effects and are expensive for the people living in under-developed countries. Plant derived substances have potential application against different diseases like cancer, inflammation and viral infections.. The mechanism of action of the medicinal plants is largely unknown. Targeting gene network and miRNA using medicinal plants could help in improving the therapeutic options against cancer.. The literature from 135 articles was reviewed by using PubMed, google scholar, Science direct to find out the plants and plant-based compounds against breast cancer and also the studies reporting their mechanistic route of action both at coding and noncoding RNA levels.. Natural products act as selective inhibitors of the cancerous cells by targeting oncogenes and tumor suppressor genes or altering miRNA expression. Natural compounds like EGCG from tea, Genistein from fava beans, curcumin from turmeric, DIM found in cruciferous, Resveratrol a polyphenol and Quercetin a flavonoid is found in various plants have been studied for their anticancer activity. The EGCG was found to inhibit proliferative activity by modulating miR-16 and miR-21. Similarly, DIM was found to down regulate miR-92a which results to modulate NFkB and stops cancer development. Another plant-based compound Glyceollins found to upregulate miR-181c and miR-181d having role in tumor suppression. It also found to regulate miR-22, 29b and c, miR-30d, 34a and 195. Quercetin having anti-cancer activity induce the apoptosis through regulating miR-16, 26b, 34a, let-7g, 125a and miR-605 and reduce the miRNA expression like miR-146a/b, 503 and 194 which are involved in metastasis.. Targeting miRNA expression using natural plant extracts can have a reverse effect on cell proliferation; turning on and off tumor-inducing and suppressing genes. It can be efficiently adopted as an adjuvant with the conventional form of therapies to increase their efficacy against cancer progression.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Breast Neoplasms; Cell Proliferation; Curcumin; Female; Gene Expression Regulation, Neoplastic; Genistein; Humans; MicroRNAs; Plant Extracts; Resveratrol

Several phytochemicals have been identified for their role in modifying miRNA regulating tumor progression. miRNAs modulate the expression of several oncogenes and tumor suppressor genes including the genes that regulate tumor angiogenesis. Hypoxia inducible factor-1 alpha (HIF-1α) signaling is a central axis that activates oncogenic signaling and acts as a metabolic switch in endothelial cell (EC) driven tumor angiogenesis. Tumor angiogenesis driven by metabolic reprogramming of EC is crucial for tumor progression and metastasis in many different cancers, including breast cancers, and has been linked to aberrant miRNA expression profiles. In the current article, we identify different miRNAs that regulate tumor angiogenesis in the context of oncogenic signaling and metabolic reprogramming in ECs and review how selected phytochemicals could modulate miRNA levels to induce an anti-angiogenic action in breast cancer. Studies involving genistein, epigallocatechin gallate (EGCG) and resveratrol demonstrate the regulation of miRNA-21, miRNA-221/222 and miRNA-27, which are prognostic markers in triple negative breast cancers (TNBCs). Modulating the metabolic pathway is a novel strategy for controlling tumor angiogenesis and tumor growth. Cardamonin, curcumin and resveratrol exhibit their anti-angiogenic property by targeting the miRNAs that regulate EC metabolism. Here we suggest that using phytochemicals to target miRNAs, which in turn suppresses tumor angiogenesis, should have the potential to inhibit tumor growth, progression, invasion and metastasis and may be developed into an effective therapeutic strategy for the treatment of many different cancers where tumor angiogenesis plays a significant role in tumor growth and progression.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Chalcones; Curcumin; Disease Progression; Endothelial Cells; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; MicroRNAs; Neoplasm Invasiveness; Neoplasm Metastasis; Neovascularization, Pathologic; Oxygen; Phytochemicals; Phytotherapy; Prognosis; Reactive Oxygen Species; Resveratrol; Signal Transduction

Curcumin (Cur) is an active derivative extracted from turmeric which exerts a wide range of interactions with biomolecules through complex signaling pathways. Cur has been extensively shown to possess potential antitumor properties. In addition, there is growing body of evidence suggesting that Cur may exert potential anti-estrogen and anti-androgen activity. In vitro and in vivo studies suggest that anticancer properties of Cur against tumors affecting the reproductive system in females and males may be underlied by the Cur-mediated inhibition of androgen and estrogen signaling pathways. In this review we examine various studies assessing the crosstalk between Cur and both androgen and estrogen hormonal activity. Also, we discuss the potential chemopreventive and antitumor role of Cur in the most prevalent cancers affecting the reproductive system in females and males.

Topics: Androgen Antagonists; Animals; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Curcumin; Estrogen Receptor Modulators; Female; Genital Neoplasms, Female; Genital Neoplasms, Male; Gonadal Steroid Hormones; Humans; Male; Signal Transduction; Treatment Outcome

Breast cancer is a common malignancy with poor prognosis. Cancer cells are heterogeneous and cancer stem cells (CSCs) are primarily responsible for tumor relapse, treatment-resistance and metastasis, so for breast cancer stem cells (BCSCs). Diets are known to be associated with carcinogenesis. Food-derived polyphenols are able to attenuate the formation and virulence of BCSCs, implying that these compounds and their analogs might be promising agents for preventing breast cancer. In the present review, we summarized the origin and surface markers of BCSCs and possible mechanisms responsible for the inhibitory effects of polyphenols on BCSCs. The suppressive effects of common dietary polyphenols against BCSCs, such as curcumin, epigallocatechin gallate (EGCG) and related polyphenolic compounds were further discussed.

Topics: Antineoplastic Agents; Breast Neoplasms; Curcumin; Humans; Neoplastic Stem Cells; Polyphenols

Cancer is a life-threatening disease and is the second leading cause of death around the world. The increasing threats of drug-resistant cancers indicate that there is an urgent need for the improvement or development of more effective anticancer agents. Curcumin, a phenolic compound originally derived from turmeric plant (

Topics: Animals; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Colonic Neoplasms; Curcumin; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Prostatic Neoplasms; Signal Transduction; Structure-Activity Relationship

The discovery of Vascular Endothelial Growth Factor (VEGF), the key modulator of angiogenesis, has triggered intensive research on anti-angiogenic therapeutic modalities. Although several clinical studies have validated anti-VEGF therapeutics, with few of them approved by the U.S. Food and Drug Administration (FDA), anti-angiogenic therapy is still in its infancy. Phytochemicals are compounds that have several metabolic and health benefits. Curcumin, the yellow pigment derived from turmeric (Curcuma longa L.) rhizomes, has a wide range of pharmaceutical properties. It has also been shown to inhibit VEGF by several studies. In this review, we elaborate the effect of curcumin on VEGF and angiogenesis and its therapeutic application.

Topics: Anti-Inflammatory Agents; Antineoplastic Agents, Phytogenic; Antioxidants; Biological Availability; Breast Neoplasms; Curcumin; Humans; Macular Degeneration; Neovascularization, Pathologic; Neovascularization, Physiologic; Phytotherapy; Receptors, Vascular Endothelial Growth Factor; Vascular Endothelial Growth Factor A

Curcumin (diferuloylmethane), an orange‑yellow component of turmeric or curry powder, is a polyphenol natural product isolated from the rhizome of Curcuma longa. For centuries, curcumin has been used in medicinal preparations and as a food colorant. In recent years, extensive in vitro and in vivo studies have suggested that curcumin possesses activity against cancer, viral infection, arthritis, amyloid aggregation, oxidation and inflammation. Curcumin exerts anticancer effects primarily by activating apoptotic pathways in cancer cells and inhibiting pro‑cancer processes, including inflammation, angiogenesis and metastasis. Curcumin targets numerous signaling pathways associated with cancer therapy, including pathways mediated by p53, Ras, phosphatidylinositol‑3‑kinase, protein kinase B, Wnt‑β catenin and mammalian target of rapamycin. Clinical studies have demonstrated that curcumin alone or combined with other drugs exhibits promising anticancer activity in patients with breast cancer without adverse effects. In the present review, the chemistry and bioavailability of curcumin and its molecular targets in breast cancer are discussed. Future research directions are discussed to further understand this promising natural product.

Topics: Animals; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Curcumin; Female; Humans; Signal Transduction

Breast cancer is among the most important causes of cancer related death in women. There is a need for novel agents for targeting key signaling pathways to either improve the efficacy of the current therapy, or reduce toxicity. There is some evidence that curcumin may have antitumor activity in breast cancer. Several clinical trials have investigated its activity in patients with breast cancer, including a recent trial in breast cancer patients receiving radiotherapy, in whom it was shown that curcumin reduced the severity of radiation dermatitis, although it is associated with low bioavailability. Several approaches have been developed to increase its absorption rate (e.g., nano crystals, liposomes, polymers, and micelles) and co-delivery of curcumin with adjuvants as well as different conjugation to enhance its bioavailability. In particular, micro-emulsions is an option for transdermal curcumin delivery, which has been reported to increase its absorption. Lipid-based nano-micelles is another approach to enhance curcumin absorption via gastrointestinal tract, while polymer-based nano-formulations (e.g., poly D, L-lactic-co-glycolic [PLGA]) allows the release of curcumin at a sustained level. This review summarizes the current data of the therapeutic potential of novel formulations of curcumin with particular emphasis on recent preclinical and clinical studies in the treatment of breast cancer.

Topics: Adjuvants, Pharmaceutic; Antineoplastic Agents; Biological Availability; Breast Neoplasms; Curcumin; Cyclodextrins; Drug Carriers; Drug Compounding; Female; Humans; Hydrogels

Pathogenesis of breast cancer is paralleled by distinct alterations in the expression profile of several microRNAs (miRNAs). Recent studies have shown that miRNAs can serve as diagnostic and prognostic markers, and also as therapeutic targets in breast cancer. Curcumin is a biologically active dietary polyphenol that has emerged with strong anti-tumor properties that are also documented in breast cancer.. A multi-database electronic search was performed to provide an overview of curcumin as an adjunct therapy and miRNA modulator in breast cancer and highlight the significance of observations for the treatment of cancer therapies.. The putative anti-tumor properties of curcumin are mediated by diverse mechanisms including inhibition of cell proliferation, metastasis, migration, invasion and angiogenesis, and induction of G2/M cell cycle arrest, apoptosis and paraptosis. Recent evidence implies that curcumin can interact with several oncogenic and tumorsuppressive miRNAs involved in different stages of breast cancer. In this context, up-regulation of miR181b, miR-34a, miR-16, miR-15a and miR-146b-5p, and down-regulation of miR-19a and miR-19b have been shown following the treatment of several breast cancer cell lines with curcumin. These effects lead to the suppression of tumorigenesis and metastasis, and induction of apoptosis.. Curcumin appears as an important miRNA modulator in breast cancer. However, further investigations are warranted to elucidate the impact of curcumin on miRNA transcriptome profile of breast cancer and the resulting impact of experimental models.

Topics: Animals; Antineoplastic Agents; Biomarkers, Tumor; Breast Neoplasms; Cell Proliferation; Combined Modality Therapy; Curcumin; Humans; MicroRNAs

Worldwide breast cancer is the most common cancer in women. For many years clinicians and the researchers are examining and exploring various therapeutic modalities for breast cancer. Yet the disease has remained unconquered and the quest for cure is still going on. Present-day strategy of breast cancer therapy and prevention is either combination of a number of drugs or a drug that modulates multiple targets. In this regard natural products are now becoming significant options. Curcumin exemplifies a promising natural anticancer agent for this purpose. This review primarily underscores the modulatory effect of curcumin on the cancer hallmarks. The focus is its anticancer effect in the complex pathways of breast carcinogenesis. Curcumin modulates breast carcinogenesis through its effect on cell cycle and proliferation, apoptosis, senescence, cancer spread and angiogenesis. Largely the NFkB, PI3K/Akt/mTOR, MAPK and JAK/STAT are the key signaling pathways involved. The review also highlights the curcumin mediated modulation of tumor microenvironment, cancer immunity, breast cancer stem cells and cancer related miRNAs. Using curcumin as a therapeutic and preventive agent in breast cancer is perplexed by its diverse biological activity, much of which remains inexplicable. The information reviewed here should point toward potential scope of future curcumin research in breast cancer.

Topics: Breast Neoplasms; Cell Proliferation; Curcumin; Female; Humans

Much of the recent research in neoplasia has been focusing on the epigenetics of cancer cells, particularly as regards the search for potential molecular biomarkers that could be used for early diagnosis, effective treatment, and prognosis of several types of cancer. Carcinogenesis often starts with mutations in oncogenes and tumor suppressor genes, and it leads to anomalies in cellular processes as vital as cell cycle regulation and apoptosis. Because malignant changes arise as a result of genetic as well as epigenetic mechanisms, one possible means of intervention involves reprogramming gene expression, so as to-at least in part-revert the molecular alterations. DNA methylation and demethylation, acetylation and deacetylation of histones, and microRNAs are a few examples of the epigenetic mechanisms responsible for tumor development and progression. Many biologically active compounds present in food-including sulforaphane, curcumin, and epigallocatechin-have been found to modulate those processes. We here systematically review information on the effects of such bioactive dietary compounds on human breast cancer cell lines, and explore the mechanisms underlying those effects with a view to their potential therapeutic application.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Breast Neoplasms; Catechin; Cell Cycle; Cell Line, Tumor; Curcumin; Epigenesis, Genetic; Female; Humans; Isothiocyanates; Sulfoxides; Telomerase

Accurate. Since sCD30 levels and sCD26/sCD30 ratios may contribute to the activity of the disease, they may be used to assess ITP disease activity.. hBMSCs and hFOB1.19 cells modulate the phenotype of PC3 prostate cancer cells and the expression of CD59 by activating the RANK/RANKL/OPG signaling pathway.. Results showed that the EEG responses at lower levels of the independent variables were significantly high than at higher levels; except for oxygen content, the EEG responses at lower levels were considerably lower than at a higher level. It also showed that an upsurge in the physical demand increased lifting frequency and replication and caused decreasing in alpha power, theta/beta, alpha/beta, (theta + alpha)/beta, (theta + alpha)/(alpha + beta) and increasing in the theta power and the gamma power. Furthermore, several interactions among independent variables had significant effects on the EEG responses.. The EEG implementation for the investigation of neural responses to physical demands allows for the possibility of newer nontraditional and faster methods of human performance monitoring. These methods provide effective and reliable results as compared to other traditional methods. This study will safeguard the physical capabilities and possible health risks of industrial workers. And the applications of these tasks can occur in almost all working environments (factories, warehouses, airports, building sites, farms, hospitals, offices, etc.) that are at high altitudes. It can include lifting boxes at a packaging line, handling construction materials, handling patients in hospitals, and cleaning.

Topics: Action Potentials; Adolescent; Adult; Aged; Alanine Transaminase; Analgesics; Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Antioxidants; Apoptosis; Arrhythmias, Cardiac; Atrial Fibrillation; Biological Transport; Biomarkers; Blood Gas Analysis; Blood-Brain Barrier; Blotting, Western; Bone and Bones; Bone Marrow; Bone Neoplasms; Brain; Breast Neoplasms; Calcium; Carbon Tetrachloride; Cartilage, Articular; Case-Control Studies; CD59 Antigens; CDC2 Protein Kinase; Celastrus; Cell Cycle; Cell Division; Cell Line; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chemical Fractionation; Colitis, Ulcerative; Colon; Computer Simulation; Curcumin; Cyclin B1; Cymenes; Cytokines; Dextran Sulfate; Dipeptidyl Peptidase 4; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Ectodysplasins; Electroencephalography; Endothelial Cells; Epithelial Cells; Epithelial-Mesenchymal Transition; Exosomes; Female; Flavonoids; G2 Phase; Gene Expression Regulation; Glial Cell Line-Derived Neurotrophic Factor; Heart Atria; Heart Conduction System; Heart Ventricles; HeLa Cells; Hemodynamics; Humans; Image Interpretation, Computer-Assisted; Indoles; Inflammation; Interleukin-1beta; Interleukin-6; Iridoid Glycosides; Ki-1 Antigen; Lens, Crystalline; Lifting; Liver; Liver Cirrhosis; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred ICR; Microelectrodes; Middle Aged; Models, Cardiovascular; Multiparametric Magnetic Resonance Imaging; Myeloid Differentiation Factor 88; NADPH Oxidase 1; Neoplasm Grading; NF-kappa B; Osteoarthritis; Osteoblasts; Osteoclasts; Oxidative Stress; Oxygen; Patch-Clamp Techniques; PC-3 Cells; Permeability; Peroxidase; Plant Extracts; Plant Leaves; Prostate; Prostatic Neoplasms; Protective Agents; Proto-Oncogene Proteins c-akt; Psychophysics; Purpura, Thrombocytopenic, Idiopathic; Rabbits; Rats; Rats, Sprague-Dawley; Recovery of Function; Retrospective Studies; RNA, Long Noncoding; ROC Curve; Safety; Shoes; Signal Transduction; Sodium; Sonication; Spinal Cord; Spinal Cord Injuries; Syringa; Tight Junctions; Tissue Inhibitor of Metalloproteinase-1; Toll-Like Receptor 2; Transforming Growth Factor beta2; Transient Receptor Potential Channels; Tumor Microenvironment; Tumor Necrosis Factor-alpha; Umbilical Cord; Up-Regulation; Ventricular Function; Young Adult

Breast cancer is among the most common malignant tumors. It is the second leading cause of cancer mortality among women in the United States. Curcumin, an active derivative from turmeric, has been reported to have anticancer and chemoprevention effects on breast cancer. Curcumin exerts its anticancer effect through a complicated molecular signaling network, involving proliferation, estrogen receptor (ER), and human epidermal growth factor receptor 2 (HER2) pathways. Experimental evidence has shown that curcumin also regulates apoptosis and cell phase-related genes and microRNA in breast cancer cells. Herein, we review the recent research efforts in understanding the molecular targets and anticancer mechanisms of curcumin in breast cancer.

Topics: Antineoplastic Agents; Biological Products; Breast Neoplasms; Curcumin; Female; Humans; Signal Transduction; United States

MicroRNAs (miRNAs) are a set of non-coding small RNA molecules that play a critical role in regulation of protein coding genes in cells. MiRNAs have been extensively studied as novel biomarkers, therapeutic targets, and new drugs in various human diseases. Breast cancer is a one of the leading tumor types significantly affecting women health worldwide. Over the past decade, a number of natural agents, such as paclitaxel and curcumin, have been applied for treatment and prevention of breast cancer due to their relatively low toxicity. However, the mechanisms of action have not been completely understood. Investigation on miRNAs is able to potentially provide a novel insight into better understanding the anticancer activities of these natural products. Given that a single miRNA can target multiple genes, theoretically, those genes involved in a certain phenotype can be clustered with one or a few miRNAs. Therefore, pleiotropic activities of natural agents should be interpreted by interactions between selected miRNAs and their targets. In this review, we summarize the latest publications related to the alterations of miRNAs by two natural agents (paclitaxel and curcumin) that are currently used in intervention of breast cancer, and conclude that the mechanism involving the regulation of miRNA expression is one of the keys to understand pleiotropic activities of natural agents.

Topics: Animals; Antineoplastic Agents; Biological Products; Breast Neoplasms; Curcumin; Female; Humans; MicroRNAs; Paclitaxel

Cancer is the second largest leading cause of death worldwide and breast cancer is the most prevailing cause of mortality among all cases of malignant neoplastic disease in adult females. The incidence rate of breast malignant neoplastic disease is predominantly higher in Western women, when compared to women in Asian nations. The definitive reason for this conflict is even unknown, but dietary factors have been conceived to account for approximately 30% of cancers in Western nations. It has been hypothesized that ethnicity, including use of a variety of spices in the food would be a major reason. Among all spices, turmeric (Curcuma longa) has been proven for its better anticancer potential. In this review different molecular mechanisms including cell cycle arrest; G0/G1 and/or G2/M phase cell cycle arrest by up-regulating Cdk inhibitor, p21/WAF/CIPI and p53, inhibition of transcriptional factors; NFκB, AP-1, TNFα, IL, STAT-3, and PPAR-γ, downstream gene regulation; c-myc, Bcl-2, COX-2, NOS, Cyclin D1, TNFα, interleukins and MMP-9, growth factors; bFGF, EGF, GCSF, IL-8, PDGF, TGFα, TNF, VEGF and cell adhesion molecules; fibronectin, vitronectin, and collagen which are involved in angiogenesis and metastasis, alsothe effectiveness of curcumin, when given in combination with chemotherapeutics like cyclophosphamide, doxorubicin, mitomycin etc. in treating breast cancer have been reviewed.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cell Cycle; Cell Proliferation; Chemotherapy, Adjuvant; Curcumin; Female; Humans

Breast cancer is the most common malignant cancer among women, both in Poland and worldwide. Due to the constantly increasing number of breast cancer cases, it is vital to develop effective activities in primary and secondary prevention. One of the promising methods of best value, connecting both types of cancer prevention, appears to be chemoprevention. Chemoprevention uses natural or synthetic compounds to inhibit, delay or reverse the process of carcinogenesis. Among ingredients of natural origin, great attention is paid to curcumin - a broad-spectrum anti-cancer polyphenol derivative, extracted from the rhizome of Curcuma longa L. Curcumin has a number of chemopreventive properties such as anti-inflammatory activity, induction of apoptosis, inhibition of angiogenesis as well as tumor metastasis. Numerous in vitro and in vivo studies have demonstrated the mentioned anti-cancer effect in the epithelial breast cell line MCF-10A and in the epithelial breast cell lines MCF-7, BT-474, SK-BR-3-hr and MDA-MB-231. The main problem associated with the use of curcumin as a chemopreventive agent in humans is its low absorption from the gastrointestinal tract, poor solubility in body fluids and low bioavailability. Current studies are underway to increase the bioavailability and effectiveness of curcumin in vivo. Good results in the prevention and the treatment of breast cancer could be ensured by curcumin nanoparticles coated with albumin, known as nanocurcumin. The studies using nanocurcumin, however, are still in the preclinical stage, which is why there is a need to conduct extensive long-term randomized clinical trials to determine its effectiveness.

Topics: Anti-Inflammatory Agents; Antineoplastic Agents; Apoptosis; Biological Availability; Breast Neoplasms; Chemoprevention; Curcumin; Female; Humans; Neovascularization, Pathologic

Curcumin, the active ingredient of turmeric (curry spice), is believed to be associated with reducing the incidence of breast cancers in Asian countries. Anti-cancer efficacy of curcumin and analogs has been tested in pre-clinical studies in some cancer models including breast cancer. These studies reported promising results in inhibiting human cancer cell proliferation and tumorigenesis in animal models. Both in vitro and in vivo studies have shown that curcumin and its analogs target critical genes associated with angiogenesis, apoptosis, cell cycle, and metastasis. The inhibition of human breast cancer cell growth by curcumin is mediated via certain signaling cascades including the modulation of the NF-κB signaling pathway. Epidemiological and experimental data also demonstrated the efficacy of curcumin in chemoprevention and reversing chemo-resistance of tumors of certain cancers. This review summarizes the studies revealing the preventive and therapeutic effects of curcumin and its analogs with an emphasis on multi-targeted biological and molecular effects in a breast cancer model.

Topics: Animals; Anticarcinogenic Agents; Antineoplastic Agents; Breast Neoplasms; Curcumin; Female; Humans; Mammary Neoplasms, Experimental

Breast cancer remains the leading cause of cancer death among females worldwide. It signifies a shift from the previous decade during which the most common cause of cancer death was cervical cancer. Current treatment modalities, including surgery, radiotherapy, and adjuvant chemotherapy or hormone therapy, have not been successful enough to impart significant improvement in the morbidity or mortality of breast cancer. This cancer is highly resistant to chemotherapy as no effective treatment exists for advanced disease conditions. Moreover, there is a dearth of ideal protein biomarkers of breast cancer in plasma or serum that can be used with desired sensitivity and specificity. Along with the existing therapeutic modalities of breast cancer the focus of researchers and clinicians have shifted towards the exploration of the preventive and therapeutic uses of natural products, including dietary phytoconstituents. Curcumin, the principal active component of Indian curry spice turmeric, has been found to exert preventive and therapeutic effects in various cancers. This is, in part, due to its ability to influence a diverse range of molecular targets and signaling pathways. The ability of curcumin to enhance the efficacy of existing chemotherapeutic agents is an added advantage. The current review critically analyzes various aspects of curcumin-related research conducted for molecular understanding of its efficacy in in vitro and in vivo models of breast cancer. The article also highlights recent developments with synthetic analogs of curcumin and nanocurcumin which are in the horizon of next generation targeted therapy with curcumin in breast cancer.

Topics: Animals; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cell Line, Tumor; Chemoprevention; Curcumin; Female; Humans; Signal Transduction

Cancer is the second leading cause for mortality in US only after heart disease and lacks a good or effective therapeutic paradigm. Despite the emergence of new, targeted agents and the use of various therapeutic combinations, none of the treatment options available is curative in patients with advanced cancer. A growing body of evidence is supporting the idea that human cancers can be considered as a stem cell disease. Malignancies are believed to originate from a fraction of cancer cells that show self renewal and pluripotency and are capable of initiating and sustaining tumor growth. The cancer-initiating cells or cancer stem cells were originally identified in hematological malignancies but is now being recognized in several solid tumors. The hypothesis of stem cell-driven tumorigenesis raises questions as to whether the current treatments, most of which require rapidly dividing cells are able to efficiently target these slow cycling tumorigenic cells. Recent characterization of cancer stem cells should lead to the identification of key signaling pathways that may make cancer stem cells vulnerable to therapeutic interventions that target drug-effluxing capabilities, anti-apoptotic mechanisms, and induction of differentiation. Dietary phytochemicals possess anti-cancer properties and represent a promising approach for the prevention and treatment of many cancers.

Topics: AC133 Antigen; Antigens, CD; Breast Neoplasms; Colonic Neoplasms; Curcumin; Female; Glycoproteins; Hedgehog Proteins; Humans; Neoplastic Stem Cells; Pancreatic Neoplasms; Peptides; Protein Serine-Threonine Kinases; Receptors, Notch; Resveratrol; Signal Transduction; Stilbenes

Although traditional medicines have been used for thousands of years, for most such medicines neither the active component nor their molecular targets have been very well identified. Curcumin, a yellow component of turmeric or curry powder, however, is an exception. Although inhibitors of cyclooxygenase-2, HER2, tumor necrosis factor, EGFR, Bcr-abl, proteosome, and vascular endothelial cell growth factor have been approved for human use by the United States Food and Drug Administration (FDA), curcumin as a single agent can down-regulate all these targets. Curcumin can also activate apoptosis, down-regulate cell survival gene products, and up-regulate p53, p21, and p27. Although curcumin is poorly absorbed after ingestion, multiple studies have suggested that even low levels of physiologically achievable concentrations of curcumin may be sufficient for its chemopreventive and chemotherapeutic activity. Thus, curcumin regulates multiple targets (multitargeted therapy), which is needed for treatment of most diseases, and it is inexpensive and has been found to be safe in human clinical trials. The present article reviews the key molecular mechanisms of curcumin action and compares this to some of the single-targeted therapies currently available for human cancer.

Topics: Animals; Antineoplastic Agents; Apoptosis; Biological Availability; Breast Neoplasms; Cell Division; Cell Line, Tumor; Cell Survival; Curcumin; Humans; Lymphoma; Models, Animal; Neoplasm Metastasis; Spices; United States; United States Food and Drug Administration

Because most cancers are caused by dysregulation of as many as 500 different genes, agents that target multiple gene products are needed for prevention and treatment of cancer. Curcumin, a yellow coloring agent in turmeric, has been shown to interact with a wide variety of proteins and modify their expression and activity. These include inflammatory cytokines and enzymes, transcription factors, and gene products linked with cell survival, proliferation, invasion, and angiogenesis. Curcumin has been found to inhibit the proliferation of various tumor cells in culture, prevents carcinogen-induced cancers in rodents, and inhibits the growth of human tumors in xenotransplant or orthotransplant animal models either alone or in combination with chemotherapeutic agents or radiation. Several phase I and phase II clinical trials indicate that curcumin is quite safe and may exhibit therapeutic efficacy. These aspects of curcumin are discussed further in detail in this review.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Breast Neoplasms; Cell Proliferation; Clinical Trials as Topic; Curcumin; Gastrointestinal Neoplasms; Humans; Interleukins; MAP Kinase Signaling System; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; NF-kappa B; PPAR gamma; Signal Transduction; STAT Transcription Factors; Transcription Factor AP-1; Vascular Endothelial Growth Factor A

In this clinical trial, we evaluated Alpha® ointment efficacy in prevention of capecitabine induced hand-foot syndrome (HFS) in patients with gastrointestinal or breast cancers, for the first time.. During this pilot, randomized, triple-blinded, placebo-controlled clinical trial, the effect of Alpha® ointment (Lawsonia inermis 3 g and Curcuma longa 0.15 g/ 30 g) was assessed. It was applied on the palms and the soles, two times daily starting at the first day of chemotherapy for 4 consecutive courses. The severity of HFS was assessed at the end of the chemotherapy courses based on World Health Organization (WHO) scale and scored between 0-4.. Ninety eligible patients were included randomly in the treatment or placebo group. Median WHO HFS grade was not significantly different between the two groups, during the follow-up period (P > 0.05). In the weekly assessment, the scores increased meaningfully in both the placebo and treatment groups, but there was a delay in HFS occurrence and deterioration in Alpha ointment group based on post hoc analysis.. Administration of Alpha® ointment containing henna and curcumin could not significantly prevent capecitabine induced HFS during 4 courses of treatment, but can somewhat delay its occurrence in patients with gastrointestinal or breast cancer.

Topics: Antimetabolites, Antineoplastic; Breast Neoplasms; Capecitabine; Curcumin; Female; Hand-Foot Syndrome; Humans; Lawsonia Plant; Ointments

Despite advances in medical technology, radiation-induced dermatitis occurs in 95% of cancer patients receiving radiation therapy. Currently, there is no standard and effective treatment for the prevention or control of radiation dermatitis. The aim of this study was to determine the efficacy of nano-curcumin in alleviating the radiation-induced skin reactions (RISRs) in breast cancer patients.. A randomized, triple-blinded, placebo-controlled clinical trial was performed on 42 patients with breast cancer. The patients were randomly allocated to receive radiotherapy plus placebo (control group) and radiotherapy plus 80 mg/day nano-curcumin capsules (treatment group) up to two weeks after the end of treatment. Then, the RISRs (graded by the radiation therapy oncology group (RTOG) scale) and pain level of the patients were evaluated at baseline and weekly. Finally, the results were analyzed by T-test and Pearson chi-square test.. According to the RTOG scale, 0%, 14.28%, and 85.71% of patients in the control group showed grades 0, 1, and 2 RISRs, respectively. In the treatment group, it was observed that 9.52%, 47.61%, and 42.85% of patients had grades 0, 1, and 2 RISRs, respectively. Compared to the control group, it was found that concomitant use of the nano-curcumin supplement did not significantly reduce the RISR severity during the first to sixth weeks (P > 0.05); however, there was a significant difference at week 7 (P = 0.01). Moreover, the patient-reported pain, as the secondary endpoint, was significantly reduced in the treatment group compared with the control group (P < 0.05).. In general, it was found that the administration of nano-curcumin could alleviate radiation- induced skin toxicity of breast cancer patients, but this effect was not significant.

Topics: Breast Neoplasms; Curcumin; Double-Blind Method; Female; Humans; Pain; Radiodermatitis; Radiopharmaceuticals

Unprecedented community containment measures were taken following the recent outbreak of COVID-19 in Italy. The aim of the study was to explore the self-reported future compliance of citizens with such measures and its relationship with potentially impactful psychological variables.. An online survey was completed by 931 people (18-76 years) distributed across the Italian territory. In addition to demographics, five dimensions were measured: self-reported compliance with containment measures over time (today, at 7, 14, 30, 60, 90, and 180 days from now) at three hypothetical risk levels (10, 50, 90% of likelihood of contracting the COVID-19), perceived risk, generalized anxiety, intolerance of uncertainty, and relevance of several psychological needs whose satisfaction is currently precluded.. The duration of containment measures plays a crucial role in tackling the spread of the disease as people will be less compliant over time. Psychological needs of citizens impacting on the compliance should be taken into account when planning an easing of the lockdown, along with interventions for protecting vulnerable groups from mental distress.. La apendicitis aguda (AA) es la urgencia quirúrgica abdominal más frecuente. No encontramos estudios específicos que evalúen el impacto de la pandemia causada por el coronavirus 2 (SARS-Cov-2) sobre la AA y su tratamiento quirúrgico. Analizamos la influencia de esta nueva patología sobre la AA.. Estudio observacional retrospectivo en pacientes intervenidos por AA desde enero hasta abril de 2020. Fueron clasificados según el momento de la apendicectomía, antes de la declaración del estado de alarma (Pre-COVID19) y después de la declaración del estado de alarma (Post-COVID19) en España. Se evaluaron variables demográficas, duración de la sintomatología, tipo de apendicitis, tiempo quirúrgico, estancia hospitalaria y complicaciones postoperatorias.. La pandemia por SARS-Cov-2 influye en el momento de diagnóstico de la apendicitis, así como en su grado de evolución y estancia hospitalaria. La peritonitis fue lo más frecuentemente observado. Una sospecha y orientación clínica más temprana, es necesaria para evitar un manejo inadecuado de este trastorno quirúrgico común.. The primary outcome is improvement in PaO. Findings will provide timely information on the safety, efficacy, and optimal dosing of t-PA to treat moderate/severe COVID-19-induced ARDS, which can be rapidly adapted to a phase III trial (NCT04357730; FDA IND 149634).. None.. The gut barrier is crucial in cirrhosis in preventing infection-causing bacteria that normally live in the gut from accessing the liver and other organs via the bloodstream. Herein, we characterised gut inflammation by measuring different markers in stool samples from patients at different stages of cirrhosis and comparing this to healthy people. These markers, when compared with equivalent markers usually measured in blood, were found to be very different in pattern and absolute levels, suggesting that there is significant gut inflammation in cirrhosis related to different immune system pathways to that seen outside of the gut. This provides new insights into gut-specific immune disturbances that predispose to complications of cirrhosis, and emphasises that a better understanding of the gut-liver axis is necessary to develop better targeted therapies.. La surveillance de l’intervalle QT a suscité beaucoup d’intérêt durant la pandémie de la COVID-19 en raison de l’utilisation de médicaments prolongeant l’intervalle QT et les préoccupations quant à la transmission virale par les électrocardiogrammes (ECG) en série. Nous avons posé l’hypothèse que la surveillance en continu de l’intervalle QT par télémétrie était associée à une meilleure détection des épisodes de prolongation de l’intervalle QT.. Nous avons introduit la télémétrie cardiaque en continu (TCC) à l’aide d’un algorithme de surveillance automatisée de l’intervalle QT dans nos unités de COVID-19. Les mesures automatisées quotidiennes de l’intervalle QT corrigé (auto-QTc) en fonction de la fréquence cardiaque maximale ont été enregistrées. Nous avons comparé la proportion des épisodes de prolongation marquée de l’intervalle QTc (QTc long), définie par un intervalle QTc ≥ 500 ms, chez les patients montrant une suspicion de COVID-19 ou ayant la COVID-19 qui avaient été admis avant et après la mise en place de la TCC (groupe témoin. La surveillance en continu de l’intervalle QT est supérieure à la norme de soins dans la détection des épisodes de QTc long et exige peu d’ECG. La réponse clinique aux épisodes de QTc long est sous-optimale.. Exposure to a model wildfire air pollution source modifies cardiovascular responses to HC challenge, suggesting air pollution sensitizes the body to systemic triggers.. Though the majority of HIV-infected adults who were on HAART had shown viral suppression, the rate of suppression was sub-optimal according to the UNAIDS 90-90-90 target to help end the AIDS pandemic by 2020. Nonetheless, the rate of immunological recovery in the study cohort was low. Hence, early initiation of HAART should be strengthened to achieve good virological suppression and immunological recovery.. Dust in Egyptian laying hen houses contains high concentrations of microorganisms and endotoxins, which might impair the health of birds and farmers when inhaled. Furthermore, laying hens in Egypt seem to be a reservoir for ESBL-producing Enterobacteriaceae. Thus, farmers are at risk of exposure to ESBL-producing bacteria, and colonized hens might transmit these bacteria into the food chain.. The lack of significant differences in the absolute changes and relative ratios of injury and repair biomarkers by contrast-associated AKI status suggests that the majority of mild contrast-associated AKI cases may be driven by hemodynamic changes at the kidney.. Most comparisons for different outcomes are based on very few studies, mostly low-powered, with an overall low CoE. Thus, the available evidence is considered insufficient to either support or refute CH effectiveness or to recommend one ICM over another. Therefore, further well-designed, larger RCTs are required.. PROSPERO database Identifier: CRD42016041953.. Untouched root canal at cross-section perimeter, the Hero 642 system showed 41.44% ± 5.62% and Reciproc R40 58.67% ± 12.39% without contact with instruments. Regarding the untouched area, Hero 642 system showed 22.78% ± 6.42% and Reciproc R40 34.35% ± 8.52%. Neither instrument achieved complete cross-sectional root canal debridement. Hero 642 system rotary taper 0.02 instruments achieved significant greater wall contact perimeter and area compared to reciprocate the Reciproc R40 taper 0.06 instrument.. Hero 642 achieved higher wall contact perimeter and area but, regardless of instrument size and taper, vital pulp during. The functional properties of the main mechanisms involved in the control of muscle Ca. This study showed that the anti-inflammatory effect of the iron-responsive product DHA in arthritis can be monitored by an iron-like radioactive tracer (. Attenuated vascular reactivity during pregnancy suggests that the systemic vasodilatory state partially depletes nitric oxide bioavailability. Preliminary data support the potential for MRI to identify vascular dysfunction in vivo that underlies PE. Level of Evidence 2 Technical Efficacy Stage 1 J. MAGN. RESON. IMAGING 2021;53:447-455.. La evaluación de riesgo es importante para predecir los resultados postoperatorios en pacientes con cáncer gastroesofágico. Este estudio de cohortes tuvo como objetivo evaluar los cambios en la composición corporal durante la quimioterapia neoadyuvante e investigar su asociación con complicaciones postoperatorias. MÉTODOS: Los pacientes consecutivos con cáncer gastroesofágico sometidos a quimioterapia neoadyuvante y cirugía con intención curativa entre 2016 y 2019, identificados a partir de una base de datos específica, se incluyeron en el estudio. Se utilizaron las imágenes de tomografía computarizada, antes y después de la quimioterapia neoadyuvante, para evaluar el índice de masa muscular esquelética, la sarcopenia y el índice de grasa visceral y subcutánea.. In this in vitro premature infant lung model, HF oscillation of BCPAP was associated with improved CO. Our results showed that HPC significantly promotes neurogenesis after MCAO and ameliorates neuronal injury.. Inflammatory markers are highly related to signs of systemic hypoperfusion in CS. Moreover, high PCT and IL-6 levels are associated with poor prognosis.. These findings indicate that Tetrapleura tetraptera fruit has a protective potential against stroke through modulation of redox and electrolyte imbalances, and attenuation of neurotransmitter dysregulation and other neurochemical dysfunctions. Tetrapleura tetraptera fruit could be a promising source for the discovery of bioactives for stroke therapy.

Topics: 3T3-L1 Cells; A Kinase Anchor Proteins; Acetates; Achilles Tendon; Acute Kidney Injury; Acute Pain; Acyclic Monoterpenes; Adenine Nucleotides; Adhesins, Escherichia coli; Adipocytes; Adipocytes, Brown; Adipogenesis; Administration, Inhalation; Administration, Oral; Adrenal Cortex Hormones; Adsorption; Adult; Aeromonas hydrophila; Africa; Aged; Aged, 80 and over; Agrobacterium tumefaciens; Air; Air Pollutants; Air Pollution; Air Pollution, Indoor; Algorithms; Alkaloids; Alkynes; Allosteric Regulation; Amines; Amino Acid Sequence; Amino Acids; Amino Acids, Branched-Chain; Aminoisobutyric Acids; Aminopyridines; Amyotrophic Lateral Sclerosis; Anaerobic Threshold; Angiography; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animal Distribution; Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Ankle Joint; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Inflammatory Agents; Antibodies, Bacterial; Antifungal Agents; Antimalarials; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antioxidants; Antiretroviral Therapy, Highly Active; Antiviral Agents; Aotidae; Apelin; Apoptosis; Arabidopsis Proteins; Argentina; Arginine; Artemisinins; Arthritis, Experimental; Arthritis, Rheumatoid; Arthroscopy; Aspergillus; Aspergillus niger; Asteraceae; Asthma; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; Auditory Cortex; Autoantibodies; Autophagy; Bacteria; Bacterial Infections; Bacterial Proteins; Bacterial Typing Techniques; Base Composition; Base Sequence; Basketball; Beclin-1; Benzhydryl Compounds; Benzimidazoles; Benzo(a)pyrene; Benzofurans; Benzoxazines; Bereavement; beta Catenin; beta-Lactamase Inhibitors; beta-Lactamases; beta-Lactams; Betacoronavirus; Betaine; Binding Sites; Biofilms; Biological Assay; Biological Availability; Biological Evolution; Biomarkers; Biomechanical Phenomena; Biopolymers; Biopsy; Bismuth; Blood Glucose; Blood Platelets; Blood Pressure; Body Composition; Body Weight; Bone Marrow; Bone Marrow Cells; Bone Regeneration; Boron; Botrytis; Brain Ischemia; Brain Neoplasms; Brain-Derived Neurotrophic Factor; Brazil; Breast Neoplasms; Breath Tests; Bronchoalveolar Lavage Fluid; Burkholderia; C-Reactive Protein; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Calcification, Physiologic; Calcium; Calcium Signaling; Calorimetry, Differential Scanning; Cameroon; Camptothecin; Candida; Candida albicans; Capillaries; Carbapenem-Resistant Enterobacteriaceae; Carbapenems; Carbohydrate Conformation; Carbon; Carbon Dioxide; Carbon Isotopes; Carcinoma, Ovarian Epithelial; Cardiac Output; Cardiomyopathy, Hypertrophic; Cardiotonic Agents; Cardiovascular Diseases; Caregivers; Carps; Case-Control Studies; Catalase; Catalysis; Cats; CD4 Lymphocyte Count; Cell Culture Techniques; Cell Differentiation; Cell Line, Tumor; Cell Membrane; Cell Movement; Cell Proliferation; Cell Survival; Cells, Cultured; Cellulose; Centrosome; Ceratopogonidae; Chickens; Child; China; Cholera Toxin; Choline; Cholinesterases; Chromatography, High Pressure Liquid; Chromatography, Liquid; Chromatography, Micellar Electrokinetic Capillary; Chromatography, Reverse-Phase; Chronic Disease; Cinnamates; Cities; Citrates; Climate Change; Clinical Trials, Phase III as Topic; Coal; Coal Mining; Cohort Studies; Coinfection; Colchicine; Colony Count, Microbial; Colorectal Neoplasms; Coloring Agents; Common Cold; Complement Factor H; Computational Biology; Computer Simulation; Continuous Positive Airway Pressure; Contrast Media; Coordination Complexes; Coronary Artery Bypass; Coronavirus 3C Proteases; Coronavirus Infections; Coronavirus Protease Inhibitors; Corynebacterium glutamicum; Cosmetics; COVID-19; Creatinine; Cross-Sectional Studies; Crotonates; Crystallography, X-Ray; Cues; Culicidae; Culture Media; Curcuma; Cyclopentanes; Cyclopropanes; Cymbopogon; Cystine; Cytochrome P-450 CYP2B6; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2C19 Inhibitors; Cytokines; Databases, Genetic; Death; Dendritic Cells; Density Functional Theory; Depsides; Diabetes Mellitus, Type 2; Diamond; Diarylheptanoids; Dibenzofurans; Dibenzofurans, Polychlorinated; Diclofenac; Diet; Dietary Carbohydrates; Dietary Supplements; Diffusion Magnetic Resonance Imaging; Dioxins; Diphenylamine; Disease Outbreaks; Disease Susceptibility; Disulfides; Dithiothreitol; Dizocilpine Maleate; DNA Methylation; DNA-Binding Proteins; DNA, Bacterial; Dogs; Dose-Response Relationship, Drug; Double-Blind Method; Doublecortin Protein; Drosophila melanogaster; Droughts; Drug Carriers; Drug Combinations; Drug Delivery Systems; Drug Liberation; Drug Resistance; Drug Resistance, Bacterial; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Dust; Dynactin Complex; Dysferlin; Echo-Planar Imaging; Echocardiography; Edaravone; Egypt; Elasticity; Electrodes; Electrolytes; Emodin; Emtricitabine; Endometriosis; Endothelium, Vascular; Endotoxins; Energy Metabolism; Energy Transfer; Enterobacteriaceae; Enterococcus faecalis; Enterotoxigenic Escherichia coli; Environmental Monitoring; Enzyme Inhibitors; Epidemiologic Factors; Epigenesis, Genetic; Erythrocytes; Escherichia coli; Escherichia coli Infections; Escherichia coli Vaccines; Esophageal Neoplasms; Esophagectomy; Esophagogastric Junction; Esterases; Esterification; Ethanol; Ethiopia; Ethnicity; Eucalyptus; Evidence-Based Practice; Exercise; Exercise Tolerance; Extracorporeal Membrane Oxygenation; Family; Fatty Acids; Feedback; Female; Ferric Compounds; Fibrin Fibrinogen Degradation Products; Filtration; Fish Diseases; Flavonoids; Flavonols; Fluorodeoxyglucose F18; Follow-Up Studies; Food Microbiology; Food Preservation; Forests; Fossils; Free Radical Scavengers; Freund's Adjuvant; Fruit; Fungi; Gallium; Gender Identity; Gene Expression Regulation; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Plant; Gene Knockdown Techniques; Genes, Bacterial; Genes, Plant; Genetic Predisposition to Disease; Genitalia; Genotype; Glomerulonephritis, IGA; Glottis; Glucocorticoids; Glucose; Glucuronides; Glutathione Transferase; Glycogen Synthase Kinase 3 beta; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Grassland; Guinea Pigs; Half-Life; Head Kidney; Heart Atria; Heart Rate; Heart Septum; HEK293 Cells; Hematopoietic Stem Cells; Hemodynamics; Hep G2 Cells; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Hepatocytes; Hesperidin; High-Frequency Ventilation; High-Temperature Requirement A Serine Peptidase 1; Hippocampus; Hirudins; History, 20th Century; History, 21st Century; HIV Infections; Homeostasis; Hominidae; Housing, Animal; Humans; Hydrocarbons, Brominated; Hydrogen Bonding; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydroxybutyrates; Hydroxyl Radical; Hypertension; Hypothyroidism; Image Interpretation, Computer-Assisted; Immunoconjugates; Immunogenic Cell Death; Indoles; Infant, Newborn; Infant, Premature; Infarction, Middle Cerebral Artery; Inflammation; Inflammation Mediators; Infrared Rays; Inhibitory Concentration 50; Injections, Intravenous; Interferon-gamma; Interleukin-23; Interleukin-4; Interleukin-6; Intermediate Filaments; Intermittent Claudication; Intestine, Small; Iridoid Glucosides; Iridoids; Iron; Isomerism; Isotope Labeling; Isoxazoles; Itraconazole; Kelch-Like ECH-Associated Protein 1; Ketoprofen; Kidney Failure, Chronic; Kinetics; Klebsiella pneumoniae; Lactams, Macrocyclic; Lactobacillus; Lactulose; Lakes; Lamivudine; Laparoscopy; Laparotomy; Laryngoscopy; Leucine; Limit of Detection; Linear Models; Lipid A; Lipopolysaccharides; Listeria monocytogenes; Liver; Liver Cirrhosis; Logistic Models; Longitudinal Studies; Losartan; Low Back Pain; Lung; Lupinus; Lupus Erythematosus, Systemic; Machine Learning; Macular Degeneration; Madin Darby Canine Kidney Cells; Magnetic Phenomena; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Magnetics; Malaria, Falciparum; Male; Mannans; MAP Kinase Signaling System; Mass Spectrometry; Melatonin; Membrane Glycoproteins; Membrane Proteins; Meniscectomy; Menisci, Tibial; Mephenytoin; Mesenchymal Stem Cells; Metal Nanoparticles; Metal-Organic Frameworks; Methionine; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Nude; Mice, Obese; Mice, Transgenic; Microbial Sensitivity Tests; Microcirculation; MicroRNAs; Microscopy, Video; Microtubules; Microvascular Density; Microwaves; Middle Aged; Minimally Invasive Surgical Procedures; Models, Animal; Models, Biological; Models, Molecular; Models, Theoretical; Molecular Docking Simulation; Molecular Structure; Molecular Weight; Morus; Mouth Floor; Multicenter Studies as Topic; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Muscle, Skeletal; Myocardial Ischemia; Myocardium; NAD; NADP; Nanocomposites; Nanoparticles; Naphthols; Nasal Lavage Fluid; Nasal Mucosa; Neisseria meningitidis; Neoadjuvant Therapy; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Neoplasms, Experimental; Neural Stem Cells; Neuroblastoma; Neurofilament Proteins; Neurogenesis; Neurons; New York; NF-E2-Related Factor 2; NF-kappa B; Nicotine; Nitriles; Nitrogen; Nitrogen Fixation; North America; Observer Variation; Occupational Exposure; Ochrobactrum; Oils, Volatile; Olea; Oligosaccharides; Omeprazole; Open Field Test; Optimism; Oregon; Oryzias; Osmolar Concentration; Osteoarthritis; Osteoblasts; Osteogenesis; Ovarian Neoplasms; Ovariectomy; Oxadiazoles; Oxidation-Reduction; Oxidative Stress; Oxygen; Ozone; p38 Mitogen-Activated Protein Kinases; Pakistan; Pandemics; Particle Size; Particulate Matter; Patient-Centered Care; Pelargonium; Peptides; Perception; Peripheral Arterial Disease; Peroxides; Pets; Pharmaceutical Preparations; Pharmacogenetics; Phenobarbital; Phenols; Phenotype; Phosphates; Phosphatidylethanolamines; Phosphines; Phospholipids; Phosphorus; Phosphorylation; Photoacoustic Techniques; Photochemotherapy; Photosensitizing Agents; Phylogeny; Phytoestrogens; Pilot Projects; Plant Components, Aerial; Plant Extracts; Plant Immunity; Plant Leaves; Plant Oils; Plants, Medicinal; Plasmodium berghei; Plasmodium falciparum; Platelet Activation; Platelet Function Tests; Pneumonia, Viral; Poaceae; Pogostemon; Poloxamer; Poly I; Poly(ADP-ribose) Polymerase Inhibitors; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Polycyclic Compounds; Polyethylene Glycols; Polylysine; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Population Dynamics; Portasystemic Shunt, Transjugular Intrahepatic; Positron Emission Tomography Computed Tomography; Postoperative Complications; Postprandial Period; Potassium Cyanide; Predictive Value of Tests; Prefrontal Cortex; Pregnancy; Prepulse Inhibition; Prevalence; Procalcitonin; Prodrugs; Prognosis; Progression-Free Survival; Proline; Proof of Concept Study; Prospective Studies; Protein Binding; Protein Conformation; Protein Domains; Protein Folding; Protein Multimerization; Protein Sorting Signals; Protein Structure, Secondary; Proton Pump Inhibitors; Protozoan Proteins; Psychometrics; Pulse Wave Analysis; Pyridines; Pyrrolidines; Quality of Life; Quantum Dots; Quinoxalines; Quorum Sensing; Radiopharmaceuticals; Rain; Random Allocation; Randomized Controlled Trials as Topic; Rats; Rats, Sprague-Dawley; Rats, Wistar; RAW 264.7 Cells; Reactive Oxygen Species; Receptor, Angiotensin, Type 1; Receptor, PAR-1; Receptors, CXCR4; Receptors, Estrogen; Receptors, Glucocorticoid; Receptors, Interleukin-1; Receptors, Interleukin-17; Receptors, Notch; Recombinant Fusion Proteins; Recombinant Proteins; Reducing Agents; Reflex, Startle; Regional Blood Flow; Regression Analysis; Reperfusion Injury; Reproducibility of Results; Republic of Korea; Respiratory Tract Diseases; Retrospective Studies; Reverse Transcriptase Inhibitors; Rhinitis, Allergic; Risk Assessment; Risk Factors; Rituximab; RNA, Messenger; RNA, Ribosomal, 16S; ROC Curve; Rosmarinic Acid; Running; Ruthenium; Rutin; Sarcolemma; Sarcoma; Sarcopenia; Sarcoplasmic Reticulum; SARS-CoV-2; Scavenger Receptors, Class A; Schools; Seasons; Seeds; Sequence Analysis, DNA; Severity of Illness Index; Sex Factors; Shock, Cardiogenic; Short Chain Dehydrogenase-Reductases; Signal Transduction; Silver; Singlet Oxygen; Sinusitis; Skin; Skin Absorption; Small Molecule Libraries; Smoke; Socioeconomic Factors; Soil; Soil Microbiology; Solid Phase Extraction; Solubility; Solvents; Spain; Spectrometry, Mass, Electrospray Ionization; Spectroscopy, Fourier Transform Infrared; Speech; Speech Perception; Spindle Poles; Spleen; Sporothrix; Staphylococcal Infections; Staphylococcus aureus; Stereoisomerism; Stomach Neoplasms; Stress, Physiological; Stroke Volume; Structure-Activity Relationship; Substrate Specificity; Sulfonamides; Surface Properties; Surface-Active Agents; Surveys and Questionnaires; Survival Rate; T-Lymphocytes, Cytotoxic; Tandem Mass Spectrometry; Temperature; Tenofovir; Terpenes; Tetracycline; Tetrapleura; Textiles; Thermodynamics; Thiobarbituric Acid Reactive Substances; Thrombin; Thyroid Hormones; Thyroid Neoplasms; Tibial Meniscus Injuries; Time Factors; Tissue Distribution; Titanium; Toluidines; Tomography, X-Ray Computed; Tooth; Tramadol; Transcription Factor AP-1; Transcription, Genetic; Transfection; Transgender Persons; Translations; Treatment Outcome; Triglycerides; Ubiquinone; Ubiquitin-Specific Proteases; United Kingdom; United States; Up-Regulation; Vascular Stiffness; Veins; Ventricular Remodeling; Viral Load; Virulence Factors; Virus Replication; Vitis; Voice; Voice Quality; Wastewater; Water; Water Pollutants, Chemical; Water-Electrolyte Balance; Weather; Wildfires; Wnt Signaling Pathway; Wound Healing; X-Ray Diffraction; Xenograft Model Antitumor Assays; Young Adult; Zoogloea

Some polyphenol-derived metabolites reach human breast cancer (BC) tissues at concentrations that induce cell senescence. However, this is unknown for isoflavones, curcuminoids, and lignans. Here, their metabolic profiling in normal (NT) and malignant (MT) mammary tissues of newly-diagnosed BC patients and the tissue-occurring metabolites' anticancer activity are evaluated.. Curcuminoids could be coadjuvants that might help fight BC upon regular consumption.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Phytogenic; Apoptosis; Breast Neoplasms; Capsules; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Curcumin; Dietary Supplements; Estrogen Receptor Modulators; Female; Humans; Middle Aged; Polyphenols

Breast cancer patients receiving hormonal therapies face risks of relapse, increased rates of cardiovascular events, and toxicities of therapy such as aromatase inhibitor (AI)-associated musculoskeletal symptoms (AIMSS). C-reactive protein (CRP), a marker for inflammation, is associated with breast cancer outcomes. We evaluated whether the olive-derived polyphenol hydroxytyrosol combined with omega-3 fatty acids and curcumin would reduce CRP and musculoskeletal symptoms in breast cancer patients receiving adjuvant hormonal therapies.. This prospective, multicenter, open-label, single arm, clinical trial enrolled post-menopausal breast cancer patients (n = 45) with elevated C-reactive protein (CRP) taking predominantly aromatase inhibitors to receive a combination of hydroxytyrosol, omega-3 fatty acids, and curcumin for 1 month. CRP, other inflammation-associated cytokines, and pain scores on the Brief Pain Inventory were measured before therapy, at the end of therapy and 1 month after completion of therapy.. CRP levels declined during the therapy [from 8.2 ± 6.4 mg/L at baseline to 5.3 ± 3.2 mg/L (p = 0.014) at 30 days of treatment], and remained decreased during the additional 1 month off therapy. Subjects with the highest baseline CRP levels had the greatest decrease with the therapy. Pain scores also decreased during the therapy. There were no significant adverse events.. The combination of hydroxytyrosol, omega-3 fatty acids, and curcumin reduced inflammation as indicated by a reduction in CRP and reduced pain in patients with aromatase-induced musculoskeletal symptoms. Longer studies comparing this combination to other anti-inflammatories in larger groups of patients with clinical outcome endpoints are warranted.

Topics: Adult; Aged; Aged, 80 and over; Aromatase Inhibitors; Breast Neoplasms; C-Reactive Protein; Chemotherapy, Adjuvant; Curcumin; Drug Combinations; Fatty Acids, Omega-3; Female; Humans; Inflammation; Middle Aged; Musculoskeletal Pain; Phenylethyl Alcohol; Pilot Projects; Postmenopause; Prospective Studies

Radiation dermatitis occurs in approximately 95% of patients receiving radiotherapy (RT) for breast cancer. We conducted a randomized, double-blind, placebo-controlled clinical trial to assess the ability of curcumin to reduce radiation dermatitis severity in 30 breast cancer patients. Eligible patients were adult females with noninflammatory breast cancer or carcinoma in situ prescribed RT without concurrent chemotherapy. Randomized patients took 2.0 grams of curcumin or placebo orally three times per day (i.e., 6.0 grams daily) throughout their course of RT. Weekly assessments included Radiation Dermatitis Severity (RDS) score, presence of moist desquamation, redness measurement, McGill Pain Questionnaire-Short Form and Symptom Inventory questionnaire. The 30 evaluable patients were primarily white (90%) and had a mean age of 58.1 years. Standard pooled variances t test showed that curcumin reduced RDS at end of treatment compared to placebo (mean RDS = 2.6 vs. 3.4; P = 0.008). Fisher's exact test revealed that fewer curcumin-treated patients had moist desquamation (28.6% vs. 87.5%; P = 0.002). No significant differences were observed between arms for demographics, compliance, radiation skin dose, redness, pain or symptoms. In conclusion, oral curcumin, 6.0 g daily during radiotherapy, reduced the severity of radiation dermatitis in breast cancer patients.

Topics: Adult; Breast Neoplasms; Curcumin; Double-Blind Method; Female; Humans; Middle Aged; Radiation Dosage; Radiodermatitis; Radiotherapy

Since the improvement of chemotherapy with safe molecules is needed for a better efficacy without supplementary toxicity, we investigated the feasibility and tolerability of the combination of docetaxel and curcumin, a polyphenolic derivative extracted from Curcuma longa root.. Fourteen patients were accrued in this open-label phase I trial. At the last dose level of curcumin, three dose-limiting toxicities were observed and two out of three patients at this dose level refused to continue treatment, leading us to define the maximal tolerated dose of curcumin at 8,000 mg/d. Eight patients out of 14 had measurable lesions according to RECIST criteria, with five PR and three SD. Some improvements as biological and clinical responses were observed in most patients.. Patients with advanced or metastatic breast cancer were eligible. Docetaxel (100 mg/m(2)) was administered as a 1 h i.v. infusion every 3 w on d 1 for six cycles. Curcumin was orally given from 500 mg/d for seven consecutive d by cycle (from d-4 to d+2) and escalated until a dose-limiting toxicity should occur. The primary endpoint of this study was to determine the maximal tolerated dose of the combination of dose-escalating curcumin and standard dose of docetaxel chemotherapy in advanced and metastatic breast cancer patients. Secondary objectives included toxicity, safety, vascular endothelial growth factor and tumor markers measurements and assessment of objective and clinical responses to the combination therapy.. The recommended dose of curcumin is 6,000 mg/d for seven consecutive d every 3 w in combination with a standard dose of docetaxel. From the encouraging efficacy results, a comparative phase II trial of this regimen plus docetaxel versus docetaxel alone is ongoing in advanced and metastatic breast cancer patients.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Breast Neoplasms, Male; Carcinoma; Curcumin; Diarrhea; Docetaxel; Dose-Response Relationship, Drug; Drug Administration Schedule; Feasibility Studies; Female; Follow-Up Studies; Humans; Leukopenia; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Neutropenia; Taxoids; Time Factors; Treatment Outcome

Nanotechnology attempts to solve the problem of antibiotic resistance. Zinc oxide nanoparticles and curcumin have been shown to be antimicrobial agents and promising anticancer agents, both on their own as well as in combination, and this incorporation will likely improve these properties via a possible additive effect.. In this study, the synthesis of zinc oxide nanoparticles was done by the distilled extract of Stachys byzantina via the co-precipitation method, which is an economical and eco-friendly green synthesis method. Then, curcumin was loaded to zinc oxide nanoparticles. Antibacterial efficacy of the synthesized nanoparticles was evaluated against five intracellular bacteria; moreover, cytotoxicity was evaluated on breast cancer cells.. To confirm the synthesis and characterization of the nanoparticles, some techniques, such as XRD, FTIR, FESEM, and EDX were used. In addition, the antimicrobial activity of biosynthetic zinc oxide/curcumin nanocomposites was evaluated against selected bacterial strains. The uniform spherical nature of the zinc oxide nanoparticles was observed in the FESEM images, with the particle sizes ranging from 20 to 40 nm. The EDX spectrum showed the presence of C, O, and Zn and curcumin uptake on zinc oxide nanoparticles.. The zinc oxide/curcumin nanocomposites demonstrated an effective antibacterial effect in the disk diffusion method against five bacterial species. Furthermore, the zinc oxide/ curcumin nanocomposites showed a significant inhibitory effect on the growth of breast cancer cells in the MTT test. Thus, it seems that the synthesized zinc oxide/curcumin nanocomposites have promising high potential antimicrobial and cytotoxic effects.

Topics: Anti-Bacterial Agents; Breast Neoplasms; Curcumin; Female; Humans; Nanocomposites; Plant Extracts; Stachys; Zinc Oxide

Despite remarkable development of new therapeutic strategies to improve survival rates and treatment of patients with cancer, there are still many limitations in management of patients with distant metastasis breast cancer. Therefore, the aim of this study was to investigate a novel method to enhance therapeutic efficacy of Apatinib (as a chemotherapeutic agent) by co-administration of Curcumin (as a bioactive herbal compound) in breast cancer treatment.. Effects of Apatinib, Curcumin, and their combinations (Apa-Cur) was evaluated on viability and proliferation of breast cell line (MCF7) by MTT assay. Moreover, effects of Apatinib, Curcumin, and Apa-Cur was investigated on apoptosis rate in the cancer cells. Expression levels of apoptosis-related genes (. The obtained results showed that all treatments of Apatinib, Curcumin, and Apa-Cur significantly decreased viability and proliferation of the breast cancer cells in a concentration- and time-dependent manner. However, anti-proliferation activity of Apa-Cur combination was significantly higher than Apatinib and Curcumin treatment alone. In addition, Apatinib, Curcumin, and Apa-Cur increased apoptosis percentage in the treated cancer cells through regulation of apoptosis-related genes expression.. In general, Apa-Cur combination therapy exerts more profound anti-proliferation effects on breast cancer cell than Apatinib or Curcumin monotherapy. However, further studies are required to identify other possible signaling pathways and mechanisms involved in the anticancer effects of Apatinib, Curcumin, and Apa-Cur.

Topics: Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Curcumin; Female; Humans

5-Bis[(2-fluorophenyl)methylene]-4-piperidinone (EF-24) is a curcumin analog, which was identified for its physiochemical stability and diverse pharmacological functions. In the present study, EF-24 was added to the breast cancer cell line MCF-7 and its cellular effects were characterized. The results indicated that EF-24 possessed antiproliferative and antimigratory activities on MCF-7 cells as determined by MTT assay, wound healing, and transwell assay, respectively. In addition, the autophagosomal vesicles could be detected by acridine orange staining and electron microscope analysis in EF-24-treated cells. Conversion of LC3-I to LC3-II was also investigated following EF-24 treatment of the cells. However, the expression analysis of p62 and LC3 revealed that EF-24 could inhibit autophagic flux in MCF-7 cells. Confocal microscopy suggested that EF-24 could inhibit the degradation of autophagic vesicles by blocking the fusion of autophagosomes with lysosomes. EF-24 could also induce apoptosis of MCF-7 cells as determined by Hoechst 33342 staining, flow cytometry analysis, and western blot analysis. Moreover, treatment of the cells with the autophagy inhibitor 3-MA enhanced the PARP1 cleavage of EF-24-treated MCF-7 cells, which indicated the crosstalk between autophagy and apoptosis in breast cancer cells. Additional investigation of EF-24 should be performed in future studies to assess its antiproliferation and antimigratory effects on MCF-7 cells. However, the current results provide a solid foundation for the potential in vivo anticancer activity of this compound.

Topics: Apoptosis; Autophagy; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Curcumin; Female; Humans; MCF-7 Cells

Combined chemotherapy plays an increasingly important and practical role in the clinical treatment of malignant tumor. In this study, paclitaxel (PTX) and curcumin (Cur) are simultaneously encapsulated into nanogels (termed as NG-PC)

Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Curcumin; Female; Humans; Mice; Nanogels; Paclitaxel

Breast cancer remains a major world health challenge in women. Some Breast cancers are human epidermal growth factor receptor 2 (HER2) positive. Since this protein promotes the growth of cancer cells, it remains a therapeutic target for novel drugs. This study uses

Topics: Breast Neoplasms; Curcumin; Female; Humans; Ligands; Molecular Docking Simulation; Molecular Dynamics Simulation

Curcumin (Cur) is a polyphenolic hydrophobic molecule with several biological uses, including cancer therapy. However, its widespread use in cancer treatment faces limitations due to its low solubility in acidic and neutral conditions, rapid removal from the circulatory system, and poor bioavailability. In order to overcome these challenges, a biocompatible and pH-sensitive carrier nanoplatform was designed for the specific delivery of curcumin to breast cancer cells. This nanocomposite containing polyacrylic acid (PAA), starch, and titanium dioxide (TiO

Topics: Breast Neoplasms; Curcumin; Drug Carriers; Female; Humans; MCF-7 Cells; Nanocomposites; Nanoparticles; Spectroscopy, Fourier Transform Infrared; Starch; Water

An innovative hyaluronan-based nano-delivery system is proposed for the active targeting towards ER+ breast cancer. Hyaluronic acid (HA), an endogenous and bioactive anionic polysaccharide, is functionalized with estradiol (ES), a sexual hormone involved in the development of some hormone-dependent tumors, to give an amphiphilic derivative (HA-ES) able to spontaneously self-assemble in water to form soft nanoparticles or nanogels (NHs). The synthetic strategy used to obtain the polymer derivatives and the physico-chemical properties of the obtained nanogels (ES-NHs) are reported. ES-NHs ability to entrap hydrophobic molecules has also been investigated, by loading curcumin (CUR) and docetaxel (DTX), both able to inhibit the growth of ER+ breast cancer. The formulations are studied for their capability to inhibit the growth of the MCF-7 cell line, thus evaluating their efficacy and potential as a selective drug delivery systems. Our results demonstrate that ES-NHs have not toxic effects on the cell line, and that both ES-NHs/CUR and ES-NHs/DTX treatments inhibit MCF-7 cell growth, with ES-NHs/DTX effect higher than that of free DTX. Our findings support the use of ES-NHs to deliver drugs to ER+ breast cancer cells, assuming a receptor-dependent targeting.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Curcumin; Docetaxel; Drug Carriers; Drug Delivery Systems; Estradiol; Female; Humans; Hyaluronic Acid; MCF-7 Cells; Nanogels; Nanoparticles

Constitutional

Topics: Biomarkers; BRCA1 Protein; Breast Neoplasms; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Curcumin; Female; Gene Expression Regulation, Neoplastic; Humans; Liver Neoplasms; Methylation; MicroRNAs

Breast Cancer (BC) is one of the most common and challenging cancers among females worldwide. Conventional treatments for oral cancer rely on the use of radiology and surgery accompanied by chemotherapy. Chemotherapy presents many side effects, and the cells often develop resistance to this chemotherapy. It will be urgent to adopt alternative or complementary treatment strategies that are new and more effective without these negative effects to improve the well-being of patients. A substantial number of epidemiological and experimental studies reported that many compounds are derived from natural products such as curcumin and their analogs, which have a great deal of beneficial anti-BC activity by inducing apoptosis, inhibiting cell proliferation, migration, and metastasis, modulating cancer-related pathways, and sensitizing cells to radiotherapy and chemotherapy. In the present study, we investigated the effect of the curcumin-analog PAC on DNA repair pathways in MCF-7 and MDA-MB-231 human breast-cancer cell lines. These pathways are crucial for genome maintenance and cancer prevention. MCF-7 and MDA-MB-231 cells were exposed to PAC at 10 µM. MTT and LDH assays were conducted to evaluate the effects of PAC on cell proliferation and cytotoxicity. Apoptosis was assessed in breast cancer cell lines using flow cytometry with annexin/Pi assay. The expression of proapoptotic and antiapoptotic genes was determined by RT-PCR to see if PAC is active in programming cell death. Additionally, DNA repair signaling pathways were analyzed by PCR arrays focusing on genes being related and confirmed by quantitative PCR. PAC significantly inhibited breast-cancer cell proliferation in a time-dependent manner, more on MDA-MB-231 triple-negative breast cancer cells. The flow cytometry results showed an increase in apoptotic activity. These data have been established by the gene expression and indicate that PAC-induced apoptosis by an increased Bax and decreased Bcl-2 expression. Moreover, PAC affected multiple genes involved in the DNA repair pathways occurring in both cell lines (MCF-7 and MDA-MB231). In addition, our results suggest that PAC upregulated more than twice 16 genes (ERCC1, ERCC2, PNKP, POLL, MPG, NEIL2, NTHL1, SMUG1, RAD51D, RAD54L, RFC1, TOP3A, XRCC3, XRCC6BP1, FEN1, and TREX1) in MDA-MB-231, 6 genes (ERCC1, LIG1, PNKP, UNG, MPG, and RAD54L) in MCF-7, and 4 genes (ERCC1, PNKP, MPG, and RAD54L) in the two cell lines. In silico analysis of gene-gene interaction

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Curcumin; DNA Repair; DNA Repair Enzymes; Female; Gene Expression; Humans; Phosphotransferases (Alcohol Group Acceptor); Triple Negative Breast Neoplasms; Xeroderma Pigmentosum Group D Protein

In this work, chitosan (CS), Starch (S), and Molybdenum Disulfide (MoS

Topics: Breast Neoplasms; Chitosan; Curcumin; Drug Carriers; Drug Liberation; Female; Humans; Hydrogen-Ion Concentration; Molybdenum; Nanocomposites; Nanoparticles; Spectroscopy, Fourier Transform Infrared; Starch

Numerous in vitro and in vivo studies have shown that curcumin primarily activates apoptotic pathways in cancer cells and inhibits cancer progression by modulating various molecular targets. In this study, we utilized reverse docking servers to predict 444 human proteins that may potentially be targeted by curcumin. Then, high-throughput assays were conducted by using RNA-seq technology on curcumin-treated MCF-7 (human breast cancer ER (+)) and MDA-MB-231 (human breast cancer ER(-)/TNBC) cancer cell lines. Enrichment analysis identified seven and eight significantly down-regulated signaling pathways in these two cell lines, where the enriched genes were used to construct protein-protein interaction networks. From these networks, the MCODE algorithm screened out 42 hub targets, which are core genes of the RTK-(PI3K-AKT)/(MEK/ERK1/2) crosstalk network. Genetic alteration and expression patterns of hub targets of curcumin may be closely related to the overall pathogenesis and prognosis of breast cancer. MAPKAPK3, AKT3, CDK5, IGF1R, and MAPK11 are potential prognostic markers and therapeutic targets of curcumin in patients with triple-negative breast cancer. Molecular docking and transcriptomic results confirmed that curcumin can inhibit these high-scoring targets at the protein level. Additionally, these targets can act as self-feedback factors, relying on the cascading repressive effects in the network to limit their own transcription at the mRNA level. In conclusion, the integration of transcriptomic and molecular docking approaches enables the rapid identification of dual or multiple inhibitory targets of curcumin in breast cancer. Our study provides the potential elucidation of the anti-cancer mechanism of curcumin.

Topics: Breast Neoplasms; Curcumin; Female; Humans; Molecular Docking Simulation; Phosphatidylinositol 3-Kinases; Transcriptome; Triple Negative Breast Neoplasms

Breast cancer is the second most common type of cancer worldwide and the leading cause of cancer death in women. Dietary bioactive compounds may act at different stages of carcinogenesis, including tumor initiation, promotion, and progression. Spices have been used for thousands of years and have many bioactive compounds with chemopreventive and chemotherapeutic properties. Curcumin has a multitude of beneficial biological properties, including anti-inflammatory and anticancer effects. This study investigated the effects of cotreatment with curcumin and the chemotherapeutic drug melphalan in cultured MDA-MB-231 breast cancer cells. When used alone, both curcumin and melphalan had a cytotoxic effect on breast cancer cells. Combined treatment with 11.65 µM of curcumin and 93.95 µM of melphalan (CURC/MEL) reduced cell viability by 28.64% and 72.43% after 24 h and 48 h, respectively. CURC/MEL reduced the number of colony-forming units and increased ROS levels by 1.36-fold. CURC/MEL alter cell cycle progression, induce apoptosis, and upregulate caspases-3, -7, and -9, in MDA-MB-231 cells. Cotreatment with curcumin and melphalan have anti-breast cancer cells effects and represent a promising candidate for clinical testing.

Topics: Apoptosis; Breast Neoplasms; Cell Cycle Checkpoints; Curcumin; Female; Humans; Melphalan

Chemotherapy agents often exhibit limited effectiveness due to their fast elimination from the body and non-targeted delivery. Emerging nanomaterials as drug delivery carriers open new expectancy to overcome these limitations in current chemotherapeutic treatments. In this study, we introduce and evaluate a smart pH-responsive niosomal formulation capable of delivering Doxorubicin (DOX) and Curcumin (CUR) in both individually and co-loaded forms. In particular, drug-loaded niosomes were prepared using thin-film hydration method and then characterized via different physicochemical analyses. The pH responsivity of the carrier was assessed by performing a drug release study in three different pH conditions (4, 6.5, and 7.4). Finally, the anticancer efficacy of the therapeutic compounds was evaluated through the MTT assay. Our results showed spherical particles with a size of about 200 nm and -2 mV surface charge. Encapsulation efficiency (EE%) of the nanocarrier was about 77.06 % and 79.08 % for DOX and CUR, respectively. The release study confirmed the pH responsivity of the carrier. The MTT assay results revealed about 39 % and 43 % of cell deaths after treatment with cur-loaded and dox-loaded niosomes, which increased to 74 % and 79 % after co-administration and co-loading forms of drugs, respectively, exhibiting increased anticancer efficacy by selectively delivering DOX and CUR individually or in combination. Overall, these findings suggest that our nanoformulation holds the potential as a targeted and highly effective approach for cancer management and therapy, overcoming the limitations of conventional chemotherapy drugs.

Topics: Breast Neoplasms; Curcumin; Doxorubicin; Drug Carriers; Female; Humans; Liposomes; MCF-7 Cells; Nanoparticles

Anticancer drug resistance invariably emerges and poses a significant barrier to curative therapy for various breast cancers. This results in a lack of satisfactory therapeutic medicine for cancer treatment. Herein, a universal vector system for drug-resistance breast cancer was designed to meet the needs of reversed multidrug resistance, thermo-chemotherapy, and long-term drug release behavior. The vector system comprises polycaprolactone (PCL) nanofiber mesh and magnetic nanoparticles (MNPs). PCL has excellent biocompatibility and electrospinning performance. In this study, MNPs were tailored to be thermogenic in response to an alternating magnetic field (AMF). PCL nanofiber can deliver various chemotherapy drugs, and suitable MNPs encapsulated in the nanofiber can generate hyperthermia and synergistic effect with those chemotherapy drugs. Therefore, a more personalized treatment system can be developed for different breast malignancies. In addition, the PCL nanofiber mesh (NFM) enables sustained release of the drugs for up two months, avoiding the burden on patients caused by repeated administration. Through model drugs doxorubicin (DOX) and chemosensitizers curcumin (CUR), we systematically verified the therapeutic effect of DOX-resistance breast cancer and inhibition of tumor generation in vivo. These findings represent a multifaceted platform of importance for validating strategic reversed MDR in pursuit of promoted thermo-chemotherapeutic outcomes. More importantly, the low cost and excellent safety and efficacy of this nanofiber mesh demonstrate that this can be customized multi-function vector system may be a promising candidate for refractory cancer therapy in clinical.

Topics: Breast Neoplasms; Cell Line, Tumor; Curcumin; Doxorubicin; Drug Carriers; Female; Humans; Hyperthermia, Induced; Nanoparticles

Combination therapy has been considered one of the most promising approaches for improving the therapeutic effects of anticancer drugs. This is the first study that uses two different antioxidants in full-characterized niosomal formulation and thoroughly evaluates their synergistic effects on breast cancer cells. In this study, in-silico studies of hydrophilic and hydrophobic drugs (ascorbic acid: Asc and curcumin: Cur) interactions and release were investigated and validated by a set of in vitro experiments to reveal the significant improvement in breast cancer therapy using a co-delivery approach by niosomal nanocarrier. The niosomal nanoparticles containing surfactants (Span 60 and Tween 60) and cholesterol at 2:1 M ratio were prepared through the film hydration method. A systematic evaluation of nanoniosomes was carried out. The release profile demonstrated two phases (initial burst followed by sustained release) and a pH-dependent release schedule over 72 h. The optimized niosomal preparation displayed superior storage stability for up to 2 months at 4 °C, exhibiting extremely minor changes in pharmaceutical encapsulation efficiency and size. Free dual drugs (Asc + Cur) and dual-drug loaded niosomes (Niosomal (Asc + Cur)) enhanced the apoptotic activity and cytotoxicity and inhibited cell migration which confirmed the synergistic effect of co-encapsulated drugs. Also, significant up-regulation of p53 and Bax genes was observed in cells treated with Asc + Cur and Niosomal (Asc + Cur), while the anti-apoptotic Bcl-2 gene was down-regulated. These results were in correlation with the increase in the enzyme activity of SOD, CAT, and caspase, and the levels of malondialdehyde (MDA) and reactive oxygen species (ROS) upon treatment with the mentioned drugs. Furthermore, these anti-cancer effects were higher when using Niosomal (Asc + Cur) than Asc + Cur. Histopathological examination also revealed that Niosomal (Asc + Cur) had a lower mitosis index, invasion, and pleomorphism than Asc + Cur. These findings indicated that niosomal formulation for co-delivery of Asc and Cur would offer a promising delivery system for an effective breast cancer treatment.

Topics: Antineoplastic Agents; Breast Neoplasms; Curcumin; Female; Humans; Liposomes; Polysorbates

In this study, a pH-responsive hydrogels based on laponite rapid dispersion (Lap®)/chitosan (CS)/polyvinyl alcohol (PVA) designed and was used for controlled delivery of the anticancer drug curcumin (CUR). First, it was accomplished by dissolving CUR in Lap® dispersion under the influence of the pH of the environment. Then, in the presence of Lap®CUR cross-linking was incorporated between CS and PVA polymers. The structural features of Lap®CUR/CS@PVA hydrogels are characterized using FT-IR, XRD, SEM/EDS, TEM, TGA, Zeta potential, and XPS. The in vitro drug release profiles confirmed a pH-responsive controlled release of CUR in acidic pH for all hydrogels. During 12 h, the cumulative release of CUR from Lap®CUR/0.1CS@PVA hydrogel was 27.9% and 12.3%, at pH 5.5 and 7.4, respectively. While during three days the release rate reached 48.5% and 18.5%. The CUR release kinetic from hydrogels also suggests that the kinetic data well fitted to the Korsmeyer-Peppas, diffusion-controlled and Fickian diffusion. Furthermore, in vitro cytotoxicity and DAPI staining study clearly illustrated that Lap®CUR/0.1CS@PVA hydrogel had lower cytotoxicity than CUR against MDA-MB 231 cancer cells, which confirmed the controlled release of drug through hydrogels. Meanwhile, in vitro hemolysis, antioxidant and antibacterial tests revealed that the prepared hydrogels have good blood compatibility, excellent antioxidant properties, and antibacterial activity. Based on the obtained results, the designed hydrogels could be potentially applied as pH-controlled drug delivery systems for cancer therapy.

Topics: Anti-Bacterial Agents; Antioxidants; Breast Neoplasms; Chitosan; Curcumin; Delayed-Action Preparations; Drug Carriers; Drug Liberation; Female; Humans; Hydrogels; Hydrogen-Ion Concentration; Polyvinyl Alcohol; Spectroscopy, Fourier Transform Infrared

Tumor-associated inflammation plays a vital role in cancer progression. Among the various stromal cells, cancer-associated fibroblasts are promising targets for cancer therapy. Several reports have indicated potent anti-inflammatory effects attributed to Curcumin. This study aimed to investigate whether inhibiting the inflammatory function of cancer-associated fibroblasts (CAFs) with Curcumin can restore anticancer immune responses. CAFs were isolated from breast cancer tissues, treated with Curcumin, and co-cultured with patients' PBMCs to evaluate gene expression and cytokine production alterations. Blood and breast tumor tissue samples were obtained from 12 breast cancer patients with stage II/III invasive ductal carcinoma. Fibroblast Activation Protein (FAP) + CAFs were extracted from tumor tissue, treated with 10 μM Curcumin, and co-cultured with corresponding PBMCs. The expression of smooth muscle actin-alpha (α-SMA), Cyclooxygenase-2(COX-2), production of PGE2, and immune cell cytokines were evaluated using Real-Time PCR and ELISA, respectively. Analyzes showed that treatment with Curcumin decreased the expression of genes α-SMA and COX-2 and the production of PGE2 in CAFs. In PBMCs co-cultured with Curcumin-treated CAFs, the expression of FoxP3 decreased along with the production of TGF-β, IL-10, and IL-4. An increase in IFN-γ production was observed that followed by increased T-bet expression. According to our results, Curcumin could reprogram the pro-tumor phenotype of CAFs and increase the anti-tumor phenotype in PBMCs. Thus, CAFs, as a component of the tumor microenvironment, are a suitable target for combination immunotherapies of breast cancer.

Topics: Breast Neoplasms; Cancer-Associated Fibroblasts; Cell Line, Tumor; Curcumin; Cyclooxygenase 2; Dinoprostone; Female; Fibroblasts; Humans; Inflammation; Tumor Microenvironment

Achieving selective release of chemical anticancer agents and improving therapeutic efficacy has always been a hot spot in the field of cancer research, yet how to achieve this remains a great challenge. In this work, we constructed a novel chemical anticancer agent (named MCLOP) by introducing naphthalimide into the skeleton of methylene blue (MB). Under the stimulation by cellular hypochlorous acid (HClO) and visible light, selective release of active naphthalimide can be achieved within breast cancer cell lines, the release process of which can be tracked visually using near-infrared fluorescence of MB (685 nm). More importantly, we developed biotinylated curcumin (Cur-Bio) as a new chemosensitizer, which significantly enhanced the ability of MCLOP to induce autophagic cell death of breast cancer cells. This synergistic treatment strategy exhibited an excellent anti-proliferation effect on breast cancer cells in vitro, three-dimensional (3D) cell sphere model, and mouse tumor model in vivo. This work provides a new strategy for the treatment of breast cancer and also opens new opportunities for the efficient treatment of cancer with curcumin-based chemosensitizer.

Topics: Animals; Antineoplastic Agents; Autophagic Cell Death; Biotinylation; Breast Neoplasms; Cell Survival; Curcumin; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Female; Humans; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Structure; Naphthalimides; Structure-Activity Relationship; Tumor Cells, Cultured

A real-time quartz crystal microbalance (QCM) cytosensor was first developed for dynamical and noninvasive monitoring of cell viscoelasticity for evaluation of apoptosis degree. In this work, human breast cancer cells MCF-7 and MDA-MB-231 were employed as cell model and respectively captured on the surface of QCM electrode modified with mercaptosuccinic acid and poly-l-lysine. Cell viscoelasticity was measured dynamically by real-time monitoring energy dissipation with QCM, and the dynamic diagram of the energy dissipation of MDA-MB-231 cells treated with curcumin was first obtained. The results displayed that the changes of energy dissipation in MDA-MB-231 cells and MCF-7 cells were 8.81 × 10

Topics: Apoptosis; Biosensing Techniques; Breast Neoplasms; Curcumin; Female; Humans; Viscosity

Gemini Curcumin (Gemini-Cur) is the latest nanoformulation of curcumin with a significant apoptotic effect on cancer cell lines.. This in vitro study aims to evaluate the apoptotic effects of Gemini-Cur toward MDA-MB-468 breast cancer cell lines and further the related mechanism of apoptosis.. The cytotoxicity of Gemini-Cur toward MDA-MB-468 cell lines was tested using MTT assay. Furthermore, the expression ratio of Bax/Bcl-2 was evaluated by qRT-PCR. Consequently, the protein expression of Bax/Bcl-2, survivin, and caspase-3 was measured using western blotting.. Having treated MDA-MB-468 cell lines with Gemini-Cur, the IC. The data of the current study propose that Gemini-Cur can be considered a promising candidate against triple-negative breast cancer.

Topics: Apoptosis; bcl-2-Associated X Protein; Breast Neoplasms; Caspase 3; Cell Line, Tumor; Cell Proliferation; Curcumin; Female; Humans; Proto-Oncogene Proteins c-bcl-2; Survivin; Triple Negative Breast Neoplasms

Curcumin is well known for its anticancer properties. Its cytotoxic activity has been documented in several cancer cell lines, including breast cancer. The pleiotropic activity of curcumin as an antioxidant, an antiangiogenic, antiproliferative, and pro-apoptotic, is due to its diverse targets, such as signaling pathways, protein/enzyme, or noncoding gene.. This study aimed to identify key miRNAs and mRNAs induced by curcumin in breast cancer cells MCF7, T47D (hormone positive), versus MDA-MB231 (hormone negative) using comparative analysis of global gene expression profiles.. RNA was isolated and subjected to mRNA and miRNA library sequencing to study the global gene expression profile of curcumin-treated breast cancer cells. The differential expression of gene and miRNA was performed using the DESeq R package. The enriched pathways were studied using cluster profileR, and integrated miRNA-mRNA analysis was carried out using miRtarvis and miRmapper tools.. Curcumin treatment led to upregulation of 59% TSGs in MCF7, 21% in MDA-MB-231 cells, and 36% TSGs in T47D, and downregulation of 57% oncogenes in MCF7, 76% in MDA-MB-231, and 91% in T47D. Similarly, curcumin treatment led to upregulation of 32% TSmiRs in MCF7, 37.5% in MDA-MB231, and 62.5% in T47D, and downregulation of 77% oncomiRs in MCF7, 50% in MDA-MB231 and 28.6% in T47D. Integrated analysis of miRNA-mRNA led to the identification of a common NFKB pathway altered by curcumin in all three cell lines. Analysis of uniquely enriched pathway revealed non-integrin membrane-ECM interactions and laminin interactions in MCF7; extracellular matrix organization and degradation in MDA-MB-231 and cell cycle arrest and G2/M transition in T47D.. Curcumin regulates miRNA and mRNA in a cell type-specific manner. The integrative analysis led to the detection of miRNAs and mRNAs pairs, which can be used as biomarkers associated with carcinogenesis, diagnostic, and treatment response in breast cancer.

Topics: Antioxidants; Breast Neoplasms; Curcumin; Female; Hormones; Humans; Laminin; MicroRNAs; RNA, Messenger

Canine mammary gland tumors (CMGTs) are the most frequent types of cancer in bitches and proposed as a model of human breast cancer. The anticancer effect of curcumin on human breast cancer has been extensively studied. The aim of this study was to evaluate the therapeutic effect of curcumin in two different histologies (simple carcinoma [SC] and squamous cell carcinoma [SCC]) of CMGTs. Primary canine mammary cells were isolated from the tumoral tissues surgically resected from two bitches (Case 1 and Case 2). Cell viability, apoptotic percentage, cell cycle progression and the changes in the cell morphology were evaluated. Curcumin inhibited the growth of both SC (Case 1) and SCC (Case 2) cells. However, Case 1 cells (43.48% ± 3.87% at 0.5 µM) were more sensitive to curcumin than Case 2 cells (59.36% ± 2.09% at 0.5 µM). Curcumin induced total apoptotic cell death through G0/G1 arrest, and this effect was more profound in Case 1 cells. Furthermore, cytoplasmic vacuolization, apoptotic bodies and membrane blebbing were observed in both cells following curcumin treatment. Our findings provide a novel approach for the effects of curcumin as a natural compound on CMGTs. Further investigations should be performed to investigate the molecular mechanisms of the differences in curcumin efficacy for different histological subtypes.

Topics: Animals; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Carcinoma, Squamous Cell; Cell Line, Tumor; Curcumin; Dogs; Female; Humans; Mammary Glands, Human

Although chemotherapy has been known as a powerful medication for cancer treatment over the years, there is an important necessity for designing a novel targeted drug delivery system to overcome the drawbacks of this conventional method including undesired side effects on normal cells and drug resistance. The structural differences between the surface of cancerous and normal cells allow to design and engineer targeted drug delivery systems for cancer treatment. Integrins as one of the cell surface receptors over-expressed in cancer cells could potentially be suitable candidates for targeting cancer cells. In the present study, the novel nano-carriers based on designed MiRGD peptides and graphene quantum dots (GQDs) have been used for targeted delivery of doxorubicin (Dox) and curcumin (Cur) as hydrophilic and hydrophobic drug models, respectively. The prepared nano-composites were characterized by UV-vis and photoluminescence (PL) spectroscopies, Zeta-Sizer and transmission electron microscopy (TEM). Altogether, the results of cellular uptake and fluorimetric assays performed in HUVEC and HFF cells as models of αv integrin-over-expressed cancer and normal cells, respectively, besides in-vivo study on breast cancer bearing BALB/c mice, demonstrated that the prepared nano-composites can be considered as suitable multifunctional theranostic peptideticles for targeted drug delivery and tracking.

Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Curcumin; Doxorubicin; Drug Carriers; Drug Delivery Systems; Female; Graphite; Humans; Mice; Peptides; Precision Medicine; Quantum Dots; Theranostic Nanomedicine

Dietary (poly)phenols are extensively metabolized, limiting their anticancer activity. Exosomes (EXOs) are extracellular vesicles that could protect polyphenols from metabolism. Our objective was to compare the delivery to breast tissue and anticancer activity in breast cancer cell lines of free curcumin (CUR) and resveratrol (RSV) vs. their encapsulation in milk-derived EXOs (EXO-CUR and EXO-RSV). A kinetic breast tissue disposition was performed in rats. CUR and RSV were analyzed using UPLC-QTOF-MS and GC-MS, respectively. Antiproliferative activity was tested in MCF-7 and MDA-MB-231 breast cancer and MCF-10A non-tumorigenic cells. Cell cycle distribution, apoptosis, caspases activation, and endocytosis pathways were determined. CUR and RSV peaked in the mammary tissue (41 ± 15 and 300 ± 80 nM, respectively) 6 min after intravenous administration of EXO-CUR and EXO-RSV, but not with equivalent free polyphenol concentrations. Nanomolar EXO-CUR or EXO-RSV concentrations, but not free CUR or RSV, exerted a potent antiproliferative effect on cancer cells with no effect on normal cells. Significant (p < 0.05) cell cycle alteration and pro-apoptotic activity (via the mitochondrial pathway) were observed. EXO-CUR and EXO-RSV entered the cells primarily via clathrin-mediated endocytosis, avoiding ATP-binding cassette transporters (ABC). Milk EXOs protected CUR and RSV from metabolism and delivered both polyphenols to the mammary tissue at concentrations compatible with the fast and potent anticancer effects exerted in model cells. Milk EXOs enhanced the bioavailability and anticancer activity of CUR and RSV by acting as Trojan horses that escape from cancer cells’ ABC-mediated chemoresistance.

Topics: Animals; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Curcumin; Exosomes; Female; Humans; Milk; Polyphenols; Rats; Resveratrol

Breast cancer is prevalent and diverse with significantly high incidence and mortality rates. Curcumin (Cur), a polyphenol component of turmeric, has been widely recognized as having strong anti-breast cancer activity. However, its anti-cancer efficiency is largely impaired by some of its concomitant negative properties, including its poor solubility, low cellular uptake, and severe reported side effects. Hence, the necessity arises to develop a novel low-toxic and high-efficiency targeting drug delivery system (DDS). In this study, we developed a pH-sensitive tumor self-targeting DDS (Cur@HFn) based on self-assembled HFn loaded with Cur, in which Cur was encapsulated into HFn cavity by using a disassembly/reassembly strategy, and the Cur@HFn was characterized by ultraviolet-visible (UV-vis), dynamic light scattering (DLS), and transmission electron microscope (TEM). A variety of breast cancer cell models were built to evaluate cytotoxicity, apoptosis, targeting properties, and uptake mechanism of the Cur@HFn. The pharmacodynamics was also evaluated in tumor (4T1) bearing mice after intravenous injection.

Topics: Animals; Apoferritins; Breast Neoplasms; Cell Line, Tumor; Curcumin; Drug Carriers; Female; Humans; Hydrogen-Ion Concentration; Mice

Multi-drug nanosystem has been employed in several therapeutic models due to the synergistic effect of the drugs and/or bioactive compounds, which help in tumor targeting and limit the usual side effects of chemotherapy.. In this research, we developed the amphiphilic Heparin-poloxamer P403 (HSP) nanogel that could load curcumin (CUR) and Paclitaxel (PTX) through the hydrophobic core of Poloxamer P403. The features of HSP nanogel were assessed through Fourier-transform infrared spectroscopy (FT-IR), transmission electron microscopy (TEM), differential light scattering (DLS), and critical micelle concentration (CMC). Nanogel and its dual drug-loaded platform showed high stability and spherical morphology.. The drug release profile indicated fast release at pH 5.5, suggesting effective drug distribution at the tumor site. In vitro research confirms lower cytotoxicity of HSP@CUR@PTX compared to free PTX and higher inhibition effect with MCF-7 than HSP@PTX. These results support the synergism between PTX and CUR.. HSP@CUR@PTX suggests a prominent strategy for achieving the synergistic effect of PTX and CUR to circumvent undesirable effects in breast cancer treatment.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Curcumin; Drug Carriers; Female; Heparin; Humans; Nanogels; Nanoparticles; Paclitaxel; Poloxamer; Spectroscopy, Fourier Transform Infrared

Topics: alpha-Tocopherol; Antineoplastic Agents; Breast Neoplasms; Caco-2 Cells; Curcumin; Doxorubicin; Female; Humans; MCF-7 Cells; Particle Size; Polyethylene Glycols; Vitamin E

Chitosan (Ch)-coated nanostructured lipid carriers (NLCs) have great potential for transdermal delivery with high localization of chemotherapeutics in breast cancer. This study used tetrahydrocurcumin (THC), a primary metabolite of curcumin with enhanced antioxidant and anticancer properties, as a model compound to prepare NLCs. Response surface methodology was employed to optimize THC-loaded Ch-coated NLCs (THC-Ch-NLCs) fabricated by high-shear homogenization. The optimized THC-Ch-NLCs had particle size of 244 ± 18 nm, zeta potential of -17.5 ± 0.5 mV, entrapment efficiency of 76.6 ± 0.2% and drug loading of 0.28 ± 0.01%. In vitro release study of THC-Ch-NLCs showed sustained release following the Korsmeyer-Peppas model with Fickian and non-Fickian diffusion at pH 7.4 and 5.5, respectively. THC-Ch-NLCs demonstrated significantly enhanced in vitro skin permeation, cell uptake, and remarkable cytotoxicity toward MD-MBA-231 breast cancer cells compared to the unencapsulated THC, suggesting Ch-NLCs as potential transdermal nanocarriers of THC for triple-negative breast cancer treatment.

Topics: Breast Neoplasms; Chitosan; Curcumin; Drug Carriers; Female; Humans; Lipids; Nanostructures; Particle Size

Triple Negative Breast Cancer (TNBC) is the aggressive and lethal type of breast malignancy that develops resistance to current therapies. Combination therapy has proven to be an effective strategy on TNBC. We aimed to study whether the nano-formulation of polyphenolic curcumin (Gemini-Cur) would affect the cisplatin-induced toxicity in MDA-MB-231 breast cancer cells. MDA-MB-231 cells were treated with Gemini-Cur, cisplatin and combination of Gemini-Cur/Cisplatin in a time- and dose-dependent manner. Cell viability was studied by using MTT, fluorescence microscopy and cell cycle assays. The mode of death was also determined by Hoechst staining and annexin V-FITC. Real-time PCR and western blotting were employed to detect the expression of BAX and BCL-2 genes. Our data demonstrated that Gemini-Cur significantly sensitizes cancer cells to cisplatin (combination index ≤ 1) and decreases IC50 values in comparison with Gemini-cur or cisplatin. Further studies confirmed that Gemini-Cur/Cisplatin suppresses cancer cell growth through induction of apoptosis (p < 0.001). In conclusion, the data confirm the synergistic effect of polyphenolic curcumin on cisplatin toxicity and provide attractive strategy to attain its apoptotic effect on TNBC.

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cisplatin; Curcumin; Female; Humans; Polyphenols; Triple Negative Breast Neoplasms

Combinational therapy is a new trend in medical sciences to achieve a maximum therapeutic response of the drugs with a comparatively low incidence of severe adverse effects. To overcome the challenges of conventional formulations for cancer chemotherapy, a polymer-based complex nanomicellar system, namely CPM-DD, was developed co-delivering the anti-cancer agent doxorubicin (DOX) and potent antioxidant dimethoxycurcumin (DiMC). The optimal mass ratio of DOX/DiMC in CPM-DD was determined as 1:6 due to the synergistic antiproliferative effect from

Topics: Animals; Breast Neoplasms; Curcumin; Doxorubicin; Drug Carriers; Female; Humans; Mice; Mice, Nude; Micelles; Nanoparticles; Polymers; Tissue Distribution

In the course of chemotherapy for breast cancer, doxorubicin (DOX) is one of the most commonly prescribed agents. However, it has been recognized as clinically circumscribed on account of its poor selectivity and toxic reactions to normal tissues. Fortunately, the distinct merit of photochemical-responsive nanoparticle delivery systems to enhance cellular drugs uptake through localized concentration, adequate selective and minimizing systemic toxicity has aroused substantial interest recently. In this study, we synthesized photochemical-responsive nanoparticle by incorporating DOX, curcumin (CUR), and perfluorooctyl bromide (PFOB) into poly(lactic-co-glycolic acid) (PLGA) via double emulsification (DOX-CUR-PFOB-PLGA). The synthesized composite nanoparticles, which featured good ultrasound imaging, engendered photochemical activation for drug release when given laser irradiation. Cumulative release rates for DOX were 76.34%, and for CUR were 83.64%, respectively. Also, MCF-7 cells displayed significant intracellular DOX uptake and reactive oxygen species (ROS) levels, degraded cytoskeleton, and decreased cell growth and migration capacity. At the molecular level, cellular pAKT levels decreased, which resulted in downregulated HIF-1α and BAX/BCl-2 levels, leading to Caspase-3 activation and thus induction of apoptosis. Therefore, the photochemical-responsive nanoparticles possess the potential to elicit apoptosis in MCF-7 cells via enhanced DOX uptake.

Topics: Apoptosis; Breast Neoplasms; Cell Proliferation; Curcumin; Doxorubicin; Drug Carriers; Female; Humans; MCF-7 Cells; Nanoparticles

Breast cancer is a complex multifactorial disease and polymorphisms in nucleotide excision repair pathway are associated with the potential risk of breast cancer. Pathological processes linked to breast cancer are associated with oxidative stress. Catalase plays an essential role in cell defense against oxidative stress. Curcumin has antioxidant activity that can significantly reduce oxidative stress levels. The aims of this study were to determine ERCC5 rs751402 polymorphism was associated with oxidative stress in breast carcinogenesis. The impact of curcumin on catalase activity for inhibiting breast cancer progression was also studied.. The effect of ERCC5 rs751402 polymorphism on oxidative stress was studied with different H2O2 concentrations in HCC 1937 cell line for 24 h and then analysed by MTT assay. The impact of curcumin on catalase activity was studied in MCF-7 cell line treated with different curcumin concentrations for 24 h and then analysed by trypan blue exclusion assay and catalase activity assay.. It showed that this polymorphism involved in oxidative stress (p < 0.05) and curcumin caused the antiproliferative effect by the catalase activity increase (p < 0.05).. Our study indicated that ERCC5 rs751402 polymorphism may contribute to the etiology of breast carcinogenesis about the failure of oxidative stress protection and lead to breast carcinogenesis. The antiproliferative effect of curcumin may be associated with catalase activity and protect breast carcinogenesis.

Topics: Antioxidants; Breast Neoplasms; Carcinoma, Hepatocellular; Catalase; Cell Transformation, Neoplastic; Curcumin; DNA-Binding Proteins; Endonucleases; Female; Humans; Hydrogen Peroxide; Liver Neoplasms; MCF-7 Cells; Nuclear Proteins; Oxidative Stress; Polymorphism, Genetic; Transcription Factors

Dietary polyphenols such as quercetin and curcumin have been extensively administered to patients with cancer in the form of herbal supplements. They may have a synergistic anticancer effect; however, a risk of pharmacokinetic interactions with selective CDK-4/6 inhibitors that are metabolized by the CYP3A4 enzyme exists. Considering these pharmacokinetic aspects, the current study examined the effects of curcumin and quercetin on human CYP3A4 to ascertain CYP3A4-mediated herb-drug interactions with CDK inhibitors. In this study, using in silico methods and CYP3A4 inhibition kinetics in human liver microsomes and recombinant CYP3A4 enzymes, the effects of concentration-dependent inhibition of CYP3A4 by quercetin and curcumin on CDK inhibitors metabolism were examined. Based on our in-silico docking findings, curcumin and quercetin were considerably bound to CYP3A4 protein and displace CDK inhibitors from the CYP3A4 substrate binding domain. The IC

Topics: Breast Neoplasms; Curcumin; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Female; Herb-Drug Interactions; Humans; Microsomes, Liver; Midazolam; Molecular Dynamics Simulation; Polyphenols; Quercetin

Breast cancer is one of the most common types of cancer diagnosed and the second leading cause of death among women. Breast cancer susceptibility proteins of type 1 and 2 are human tumor suppressor genes. Genetic variations/mutations in these two genes lead to overexpression of human breast tumor suppressor genes (e.g., BRCA1, BRCA2), which triggers uncontrolled duplication of cells in humans. In addition, multidrug resistance protein 1 (MDR1), an important cell membrane protein that pumps many foreign substances from cells, is also responsible for developing resistance to cancer chemotherapy.. The binding affinity of the compounds was analyzed, and it was observed that they had a better binding affinity for the target proteins than the standard drug 5-fluorouracil. Among the compounds analyzed,

Topics: Apigenin; BRCA1 Protein; BRCA2 Protein; Breast Neoplasms; Citrinin; Curcumin; Female; Fluorouracil; Genes, BRCA1; Genetic Predisposition to Disease; Germ-Line Mutation; Humans; Molecular Docking Simulation

As the most common cancer in women, efforts have been made to develop novel nanomedicine-based therapeutics for breast cancer. In the present study, the in silico curcumin (Cur) properties were investigated, and we found some important drawbacks of Cur. To enhance cancer therapeutics of Cur, three different nonionic surfactants (span 20, 60, and 80) were used to prepare various Cur-loaded niosomes (Nio-Cur). Then, fabricated Nio-Cur were decorated with folic acid (FA) and polyethylene glycol (PEG) for breast cancer suppression. For PEG-FA@Nio-Cur, the gene expression levels of Bax and p53 were higher compared to free drug and Nio-Cur. With PEG-FA-decorated Nio-Cur, levels of Bcl2 were lower than the free drug and Nio-Cur. When MCF7 and 4T1 cell uptake tests of PEG-FA@Nio-Cur and Nio-Cur were investigated, the results showed that the PEG-FA-modified niosomes exhibited the most preponderant endocytosis. In vitro experiments demonstrate that PEG-FA@Nio-Cur is a promising strategy for the delivery of Cur in breast cancer therapy. Breast cancer cells absorbed the prepared nanoformulations and exhibited sustained drug release characteristics.

Topics: Breast Neoplasms; Curcumin; Drug Carriers; Drug Delivery Systems; Female; Folic Acid; Humans; Liposomes; Nanoparticles; Polyethylene Glycols

Breast cancer is the second major cause of death worldwide among women. Co-delivery of anticancer drugs and nucleic acids targeting the apoptosis pathway could be a promising new approach.. In the present study, we synthesized a novel nanostructure for the co-delivery of curcumin and siRNA to breast cancer cells. Curcumin-loaded polylactic-co-glycolic acid (PLGA) was synthesized using an O/W emulsion-solvent diffusion method. It was coated with polyethylenimine (PEI) and subsequently complexed with Bcl-2 siRNA. Also, nanoparticles were characterized such as zeta potential, size distribution and drug encapsulation. Finally, the cytotoxicity of NP and Bcl-2 expression was evaluated.. The curcumin-loaded PLGA nanoparticles were 70 nm in size, and increased to 84 nm after incorporation of PEI plus Bcl-2 siRNA. The encapsulation ratio of the drug in our nanoparticle was 78%. Cellular internalization of PLGA-CUR-PEI/Bcl-2 siRNA NPs was confirmed by fluorescence microscopy with the broadcasting of the fluorescence in the cytoplasm and into the nucleus. The results of the cell viability assay revealed that curcumin-loaded PLGA coated with PEI and Bcl-2 siRNA exhibited the highest cytotoxicity against the T47D cell line, while the siRNA decreased the Bcl-2 expression by 90.7%.. The co-delivery of curcumin plus Bcl-2 siRNA with the PLGA-PEI nanosystem could be a synergistic drug carrier against breast cancer cells.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Curcumin; Drug Carriers; Emulsions; Female; Glycolates; Humans; Lactic Acid; Nanoparticles; Polyethyleneimine; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; RNA, Small Interfering; Solvents

Super-paramagnetic iron oxide nanoparticles (SPIONs) are known as promising theranostic nano-drug carriers with magnetic resonance imaging (MRI) properties. Applying the herbaceous components with cytotoxic effects as cargos can suggest a new approach in the field of cancer-therapy. In this study mesoporous silica coated SPIONs (mSiO2@SPIONs) containing curcumin (CUR) and silymarin (SIL) were prepared and evaluated on breast cancer cell line, MCF-7.. Nanoparticles (NPs) were formulated by reverse microemulsion method and characterized by DLS, SEM and VSM. The in vitro drug release, cellular cytotoxicity, and MRI properties of NPs were determined as well. The cellular uptake of NPs by MCF-7 cells was investigated through LysoTracker Red staining using confocal microscopy.. The MTT results showed that the IC50 of CUR + SIL loaded mSiO2@SPIONs was reduced about 50% in comparison with that of the free drug mixture. The NPs indicated proper MRI features and cellular uptake through endocytosis.. In conclusion the prepared formulation may offer a novel theranostic system for breast cancer researches.

Topics: Breast Neoplasms; Curcumin; Female; Humans; Magnetite Nanoparticles; Nanoparticles; Silicon Dioxide; Silymarin

Topics: Antineoplastic Agents; Breast Neoplasms; Curcumin; Cyclin-Dependent Kinase 8; ErbB Receptors; Female; Humans; Molecular Docking Simulation; Receptors, Progesterone

Introduction: Chemotherapy, biotherapy, and radiotherapy play a limited but important role in treating breast cancer. For more efficient treatment, combination therapy could be an appropriate option. In this study, radiotherapy using neutron radiation emitted from a 241Am-Be neutron source, as well as biotherapy using curcumin (80 μM) was combined to investigate the efficiency of treatment towards MCF-7 breast cancer in a three dimensional (3D) culture medium.. Methods: MTT, neutral red uptake assay, nitric oxide, glutathione assay, catalase, cytochrome c, comet assay, and caspase-3 were used to determine the effect of neutron radiation and also neutron and curcumin combination on the viability of cancer cells.. Results: The results of cytotoxicity test showed that neutron irradiation with or without curcumin at 5, 10, 15, and 20 h reduced the survival of tumor cells. Moreover, the rate of apoptosis due to the neutron effect at different irradiation times enhanced with the increasing time.. Conclusion: Due to the significant anticancer effect of curcumin in 3D culture, using this molecule before or after neutron therapy is recommended.

Topics: Americium; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Curcumin; Female; Humans; Neutrons

Herein, we explore the biological properties of curcumin, quercetin, and rutin by loading them onto porous CuO nanorods (NRs). The CuO NRs were synthesized using the microwave irradiation method through a chemical reaction between CuSO

Topics: Anti-Infective Agents; Antioxidants; Breast Neoplasms; Curcumin; Escherichia coli; Female; Humans; MCF-7 Cells; Microbial Sensitivity Tests; Microwaves; Nanotubes; Quercetin; Rutin

Compared with conventional therapeutic approaches, nanomedicines are attracting a growing interest due to their better targeting ability, higher delivery efficiency, and good water solubility. However, conventional drug efficacy assessment methods are based on a two-dimensional (2D) culture approach of single cells to obtain

Topics: Bionics; Breast Neoplasms; Curcumin; Female; Humans; Nanoparticles; Printing, Three-Dimensional; Tumor Microenvironment; Water

The incidence of breast cancer continues to rise despite decades of laboratory, epidemiological and clinical research. Breast cancer is still the leading cause of cancer death in women. Cyclin D1 is one of the most important oncoproteins associated with cancer cell proliferation and is overexpressed in more than 50% of cases. Curcumin and chrysin are plant-derived components that are believed to assist in inhibiting the viability of breast cancer cells. These agents are involved in cancer cells' growth and reducing cyclin D1 expression. In this study, the hypothesis of combining curcumin and chrysin is applied to analyze the potential synergistic effect in inhibiting cancer cell proliferation and down-regulation of cyclin D1. Furthermore, applying PLGA-PEG NPs could improve the bioavailability of free curcumin and chrysin components and at the same time increases the anti-cancer potential of this compound.. PLGA-PEG NPs were synthesized via the ring-opening polymerization technique and characterized with FT-IR and FE-SEM for chemical structure and morphological characteristics, respectively. Next, curcumin and chrysin were loaded in PLGA-PEG NPs and MTT assay was performed to assess the cytotoxic effect of these agents. T-47D cells were treated with appropriate concentrations of these agents and cyclin D1 expression level was evaluated by real-time PCR.. The obtained results from FT-IR and FE-SEM techniques illustrated that curcumin and chrysin were efficiently encapsulated into PLGA-PEG NPs. Curcumin, chrysin, and curcumin-chrysin in free and nano-encapsulated forms exhibited an anti-cancer effect on T-47D cells in a time- and dose-dependent manner, especially in a combination of free and encapsulated forms demonstrated synergistic anti-cancer effects. Compared to free form, Nano-curcumin, Nano-chrysin, and Nano-combination remarkably down-regulated cyclin D1 gene expression. (p-value < 0.05).. Our results revealed that the curcumin-chrysin combination has a synergistic effect and the encapsulated form of this nano-component has more inhibition on cyclin D1 expression.
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Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Curcumin; Cyclin D1; Female; Humans; MCF-7 Cells; Nanoparticles; Polyethylene Glycols; Spectroscopy, Fourier Transform Infrared

Topics: Apoptosis; Breast Neoplasms; Curcumin; Female; G-Quadruplexes; Genes, myc; Humans; MDA-MB-231 Cells; Molecular Docking Simulation; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-myc

Cancer, which is defined as abnormal cell growth, is one of the biggest public health problems in the world. Natural compounds, such as polyphenols, are used as chemo- preventive and chemotherapeutic agents in different types of cancer owing to their antioxidant, antineoplastic, and cytotoxic properties. To improve their bioavailability and releasing behavior, hydrogel systems with high drug loadingg, stability and hydrophilic nature have been designed.. We conducted the present study to investigate the anticancer effects of curcumin and chrysin loaded in the alginate-chitosan hydrogel on breast cancer (T47D) and lung cancer (A549).. The curcumin-chrysin-loaded alginate-chitosan hydrogels were prepared through the ionic gelation mechanism utilizing CaCl2. The prepared hydrogels were studied by using the Fourier Transform Infrared Spectroscopy (FTIR) and Scanning Electron Microscopy (SEM). The MTT and DAPI staining assays were employed for cytotoxicity and apoptosis studies of curcumin-chrysin- loaded alginate-chitosan hydrogels. The effects of the curcumin-chrysin-loaded alginate-chitosan hydrogels on the cell cycle of cell lines T47D and A549 were also evaluated using the propidium iodide staining.. The curcumin-chrysin-loaded alginate-chitosan hydrogels could significantly (p<0.05) reduce the viability and induce apoptosis. Morover G2/M causes arrest of the cell cycle in both A549 and T47D cell lines.. The alginate-chitosan hydrogels could work best as an enhanced anticancer drug delivery system.

Topics: Alginates; Antineoplastic Agents; Breast Neoplasms; Cell Line; Chitosan; Curcumin; Drug Carriers; Female; Flavonoids; Humans; Hydrogels; Lung

TGFβ signaling promotes progression of bone-metastatic (BMET) breast cancer (BCa) cells by driving tumor-associated osteolysis, a hallmark of BCa BMETs, thus allowing for tumor expansion within bone. Turmeric-derived bioactive curcumin, enriched in bone via local enzymatic deconjugation of inactive circulating curcumin-glucuronides, inhibits osteolysis and BMET progression in human xenograft BCa BMET models by blocking tumoral TGFβ signaling pathways mediating osteolysis. This is a unique antiosteolytic mechanism in contrast to current osteoclast-targeting therapeutics. Therefore, experiments were undertaken to elucidate the mechanism for curcumin inhibition of BCa TGFβ signaling and the application of this finding across multiple BCa cell lines forming TGFβ-dependent BMETs, including a possible role for bioactive curcumin metabolites in mediating these effects. Immunoblot analysis of TGFβ signaling proteins in bone tropic human (MDA-SA, MDA-1833, MDA-2287) and murine (4T1) BCa cells revealed uniform curcumin blockade of TGFβ-induced Smad activation due to down-regulation of plasma membrane associated TGFβR2 and cellular receptor Smad proteins that propagate Smad-mediated gene expression, resulting in downregulation of PTHrP expression, the osteolytic factor driving in vivo BMET progression. With the exception of early decreases in TGFβR2, inhibitory effects appeared to be mediated by oxidative metabolites of curcumin and involved inhibition of gene expression. Interestingly, while not contributing to changes in Smad-mediated TGFβ signaling, curcumin caused early activation of MAPK signaling in all cell lines, including JNK, an effect possibly involving interactions with TGFβR2 within lipid rafts. Treatment with curcumin or oxidizable analogs of curcumin may have clinical relevancy in the management of TGFβ-dependent BCa BMETs.

Topics: Animals; Bone Neoplasms; Breast Neoplasms; Cell Line, Tumor; Curcumin; Female; Humans; Mice; Oxidation-Reduction; Receptor, Transforming Growth Factor-beta Type II; Signal Transduction; Smad Proteins; Transforming Growth Factor beta1

Turmeric is one of the most used herbal supplements among cancer patients. It reportedly modulates the function of CYP450 enzymes and drug transporters. This study investigates the effect of turmeric on the pharmacokinetics of paclitaxel in breast cancer patients. This is a prospective longitudinal study with 60 breast cancer patients on treatment with single-agent paclitaxel and turmeric. The patients were followed up for two consecutive chemotherapy cycles, and their blood samples were collected, first without turmeric (first cycle) and the next after a 21-day concomitant administration of 2 g/day turmeric (second cycle). Plasma samples were quantified for paclitaxel concentration using High Performance Liquid Chromatograph with UV detector (HPLC-UV) method. The sparse concentration-time data of paclitaxel were subjected to population pharmacokinetic modeling, and then noncompartmental analysis (NCA) was performed on the simulated data to estimate the pharmacokinetic parameters of paclitaxel, before and after turmeric supplementation, for comparisons. The population pharmacokinetic parameters of paclitaxel differed from before to after turmeric supplementation. NCA of simulated concentration-time profiles showed a statistically significant reduction of 7.7% and 12.1% in AUC

Topics: Breast Neoplasms; Curcuma; Dietary Supplements; Female; Humans; Longitudinal Studies; Paclitaxel; Prospective Studies

The limitations of surgery, radiotherapy, and chemotherapy in cancer treatment and the increase in the application of nanomaterials in the field of biomedicine have promoted the use of nanomaterials in combination with radiotherapy for cancer treatment.. To improve the efficiency of cancer treatment, curcumin-naringenin loaded dextran-coated magnetic nanoparticles (CUR-NAR-D-MNPs) were used as chemotherapy and in combination with radiotherapy to verify their effectiveness in treating tumors.. CUR-NAR-D-MNPs were prepared and studied by several characterization methods. Median inhibitory concentration (IC50) and cellular toxicity were evaluated by 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assay. The cell death and radiosensitization were studied by acridine orange/ethidium bromide dual staining of MCF-7 human breast cancer cells.. CUR-NAR-D-MNPs induce apoptosis and inhibited cell proliferation through reactive oxygen species (ROS) generation. CUR-NAR-D-MNPs used alone had a certain therapeutic effect on tumors. CUR-NAR-D-MNPs plus radiotherapy significantly reduced the tumor volume and led to cell cycle arrest and induction of apoptosis through modulation of P53high, P21high, TNF-αlow, CD44low, and ROShigh signalingCONCLUSIONS:CUR-NAR-D-MNPs are effective in the treatment of tumors when combined with radiotherapy, and show radiosensitization effects against cancer proliferation in vitro and in vivo.

Topics: Animals; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Proliferation; Cell Survival; Chemoradiotherapy; Curcumin; Dextrans; Female; Flavanones; Humans; Magnetite Nanoparticles; MCF-7 Cells; Mice; Radiation-Sensitizing Agents; Rats; Reactive Oxygen Species; Xenograft Model Antitumor Assays

Breast cancer is the most common cancer of women-it affects more than 2 million women worldwide. PTP1B phosphatase can be one of the possible targets for new drugs in breast cancer therapy. In this paper, we present new curcumin derivatives featuring a 4-piperidone ring as PTP1B inhibitors and ROS inducers. We performed cytotoxicity analysis for twelve curcumin derivatives against breast cancer MCF-7 and MDA-MB-231 cell lines and the human keratinocyte HaCaT cell line. Furthermore, because curcumin is a known antioxidant, we assessed antioxidant effects in its derivatives. For the most potent cytotoxic compounds, we determined intracellular ROS and PTP1B phosphatase levels. Moreover, for curcumin and its derivatives, we performed real-time microscopy to observe the photosensitizing effect. Finally, computational analysis was performed for the curcumin derivatives with an inhibitory effect against PTP1B phosphatase to assess the potential binding mode of new inhibitors within the allosteric site of the enzyme. We observed that two tested compounds are better anticancer agents than curcumin. Moreover, we suggest that blocking the -OH group in phenolic compounds causes an increase in the cytotoxicity effect, even at a low concentration. Furthermore, due to this modification, a higher level of ROS is induced, which correlates with a lower level of PTP1B.

Topics: Breast Neoplasms; Curcumin; Cytotoxins; Female; Humans; MCF-7 Cells; Neoplasm Proteins; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Proteolysis; Reactive Oxygen Species

Topics: Breast Neoplasms; Celecoxib; Curcumin; Cyclooxygenase 2 Inhibitors; Drug Therapy, Combination; Female; Humans

Curcumin is a type of plant polyphenol extracted from

Topics: Animals; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cell Line, Tumor; Combined Modality Therapy; Curcumin; Female; Glucose; Gold; HSP90 Heat-Shock Proteins; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Matrix Metalloproteinase 9; Metal Nanoparticles; Mice; Mice, Inbred BALB C; Mice, Nude; Neovascularization, Pathologic; Radiation Tolerance; Radiation-Sensitizing Agents; RNA, Messenger; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays

Breast cancer is one of the main challenging areas in cancer treatment. Natural compounds such as curcumin and berberine have been approved with anticancer effects and are more favorable to people. Here, we investigated the potential synergistic anticancer effects of these two compounds in combination with the standard cancer drug 5-FU on the growth of MCF-7 breast cancer cells.. This study tested the effects of six different treatments on cancer cell growth: A) control; B) curcumin; C) berberine; D) 5-FU; E) curcumin + berberine; and F) curcumin + berberine + 5-FU. The IC. There was a reduction in cancer cell growth and invasion, and an increase in cellular decomposition across all treatment groups compared to the control with the strongest effects seen in the combined curcumin/berberine/5-FU group. The expression levels of all tested genes were altered in all treatment groups compared to the control, with that of WNT1, CTNNB1, TCF, MTOR, AKT1, BIRC5, and CCND1 showing the most robust changes in the combined curcumin/berberine/5-FU treatment.. All treatment groups had anti-growth, anti-invasion, and pro-apoptotic effects on MCF-7 breast cancer cells in culture. In addition, all treatment groups showed changes in the expression of the genes involved in cancer cell growth and survival with the strongest effects found for the curcumin/berberine/5-FU combination. Therefore, curcumin and berberine may improve the anticancer effects of chemotherapy and these natural compounds should undergo further testing as potential adjuvants.

Topics: Apoptosis; Berberine; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Curcumin; Drug Synergism; Female; Fluorouracil; Humans

In this study, turmeric's active ingredient (Curcumin) was encapsulated into RGD modified Liposomes (RGD-Lip-Cur) its cytotoxic effect on the breast cancer cell line (MCF-7) was evaluated by MTT, flow cytometry and Caspase assay. Liposomes were characterized using transmission electron microscopy (TEM). Results demonstrated that the liposomes were spherical in shape, ranging from 70 to 100 nm. MTT assay revealed that RGD-Lip-Cur had a significant cytotoxic effect on MCF-7 cells at concentrations of 32, 16 and 4 μg/ml compared to Lip-Cur (P < 0.05) and curcumin (P < 0.01). The apoptosis assay demonstrated that RGD-Lip-Cur induces the apoptosis in MCF-7 cells (39.6% vs 40.2% for initial and secondary apoptosis) significantly more than Lip-Cur (67.7% vs 9.16% for initial and secondary apoptosis) and free curcumin (7.84% vs 38.8% for initial and secondary apoptosis). Moreover, caspase assay showed that RGD-Lip-Cur activates caspase 3/7 compared to Lip-Cur (P < 0.05) and free curcumin (P < 0.01). The RGD-Lip-Cur was similar to the control group and had no significant cytotoxicity effect. It is concluded that RGD-Lip-Cur as a novel carrier have high cytotoxicity effect on breast cancer cell line (MCF-7).

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Survival; Curcumin; Drug Delivery Systems; Female; Humans; Liposomes; MCF-7 Cells; Microscopy, Electron, Transmission; Oligopeptides; Particle Size

Curcumin (C) is a natural antioxidant which has many beneficial effects. However, poor bioavailability and less water solubility render it unsuitable as an anti-cancer drug. Herein, curcumin was delivered through Mesoporous silica nanoparticle (MSN) based drug delivery system to enhance its anticancer efficacy. Targeted delivery of curcumin in cancer cells was also achieved by conjugating hyaluronic acid (HA) on the surface of MSN. HA showed its targeting ability through the binding with CD-44 receptors in cancer cells. The synthesis of MSN-HA-C was verified by used several characterization techniques like TEM, SEM, XRD and DLS. MSN-HA-C showed diameter of ∼ 75 nm with negatively charged surface and drug loading content of 14.76 %. The synthesized nanohybrid showed MDA-MB-231 cell death by the induction of ROS, cell cycle arrest and modulation of NF-κB and Bax mediated apoptotic pathway. The nanohybrid also effectually decreased tumor volume in tumor-bearing mice compared with free C due to the increased bioavailability and higher cellular uptake of C in tumor tissue. Overall, the study offered that MSN-HA-C has increased anticancer efficacy than that of free curcumin.

Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Curcumin; Drug Carriers; Drug Delivery Systems; Female; Humans; Hyaluronic Acid; Mice; Nanoparticles; Porosity; Silicon Dioxide

The H19 long non‑coding RNA is involved in the development of tamoxifen resistance in breast cancer. However, the relationship between H19 and the metastatic potential and treatment options for tamoxifen‑resistant (TAMR) breast cancer is not completely understood. Curcumin inhibits cellular proliferation, migration and invasiveness in several cancer types, including pancreatic cancer, breast cancer and chronic myeloid leukemia. The present study aimed to investigate the role of H19 in MCF‑7/TAMR cell epithelial‑mesenchymal transition (EMT), migration and invasiveness, and to assess the ability of curcumin to inhibit H19‑mediated effects. Reverse transcription‑quantitative PCR and western blot analysis were conducted to detect the gene or protein expression. Cell Counting Kit‑8, wound healing and Transwell invasion assays were performed to estimate the capabilities of cell viability, invasion and migration. H19 overexpression enhanced MCF‑7/TAMR cell EMT, invasion and migration by upregulating Snail. Furthermore, curcumin notably decreased the expression levels of epithelial marker E‑cadherin and markedly increased the expression levels of mesenchymal marker N‑cadherin in MCF‑7/TAMR cells compared with the control group. In addition, following treatment with curcumin for 48 h, H19 expression was decreased in a dose‑dependent manner. Moreover, curcumin treatment for 48 h significantly attenuated H19‑induced alterations in N‑cadherin and E‑cadherin expression levels. Curcumin also prevented H19‑induced invasion and migration. The present study indicated that H19 may serve as a promoting factor of EMT, invasion and migration in MCF‑7/TAMR cells, suggesting that curcumin may prevent H19‑associated metastasis. Therefore, curcumin may serve as a promising therapeutic drug for patients with TAMR breast cancer.

Topics: Breast Neoplasms; Cell Movement; Cell Proliferation; Cell Survival; Curcumin; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Drug Synergism; Epithelial-Mesenchymal Transition; Female; Gene Expression Regulation, Neoplastic; Humans; MCF-7 Cells; RNA, Long Noncoding; Tamoxifen

Resistance to common chemotherapeutic agents is a frequent phenomenon in late-stage breast cancers. An ideal system capable of the co-delivery of hydrophobic and hydrophilic chemotherapeutic agents can regulate the dosage and co-localization of pharmaceutical compounds and thereby improve the anticancer efficacy. Here, for the first time, we have intercalated curcumin (Cur) into a double-layered membrane of cisplatin (Cis) liposomes to obtain a dosage controlled co-delivery formulation, capable of inducing apoptosis in breast cancer cells. The concentrations of Cur and Cis in nanoliposome (Cur-Cis@NLP) were optimized by response surface methodology (RSM); RSM optimization showed 99.81 and 23.86% entrapment efficiency for Cur and Cis, respectively. TEM analysis demonstrated the fabrication of nanoparticles with average diameter of 100 nm. The anticancer and apoptotic effects of Cur-Cis@NLPs were also evaluated using MTT assay, fluorescent staining and flow cytometry assays. Cytotoxicity assessments of various Cur-Cis@NLPs concentrations demonstrated a concentration-dependent manner. In comparison to free and liposomal Cis, Cur-Cis@NLP reduced breast cancer cells' viability (82.5%) in a significant manner at a final concentration of 32 μg.mL

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Survival; Cisplatin; Curcumin; Drug Carriers; Drug Liberation; Drug Synergism; Female; Humans; Liposomes; MCF-7 Cells; Nanoparticles

This study targets to develop curcumin-loaded polyvinyl alcohol/cellulose nanocrystals (PVA/CNCs) membrane as localized delivery system for breast/liver cancer. A novel strategy was developed for enhancing encapsulation capacity and maximizing therapeutic efficiency of curcumin-loaded PVA/CNCs membranes. Membranes were prepared by solution-casting method using citric acid as crosslinker. SEM revealed that PVA/CNCs ratio (80:20) was chosen as the optimum for loading curcumin. FT-IR indicated that, curcumin was incorporated into PVA/CNCs in amorphous-phase via intermolecular hydrogen bond between curcumin and membrane components. Curcumin showed biphasic-release through burst-release of 41% of curcumin during the first hour, followed by sustained-release of 70% and 94% during 24 h and 48 h, respectively. In vitro cytotoxicity of PVA/CNCs/Curcumin membrane exhibited a selective inhibition proliferation of breast and liver cancer cells in a concentration-dependent without any toxic effect on normal cells. At high concentration (8 mg/ml) of PVA/CNCs/Curcumin, reduced viability to 35% and 7% of MCF-7 and Huh-7 cells, respectively; meanwhile high HFB-4 normal cell viability ≥80% was investigated. Antimicrobial activity of PVA/CNCs/Curcumin was investigated by multi-drug-resistant strains, and MIC values. PVA/CNCs/Curcumin membranes with concentration (40 mg/ml) showed broad-spectrum antimicrobial activities, thus inhibited ~96-99% of microbial growth. PVA/CNCs/Curcumin membranes could be as promised anti-infective biomaterials for breast and liver cancer wound healing.

Topics: Antineoplastic Agents, Phytogenic; Biological Dressings; Breast Neoplasms; Carcinoma; Cell Cycle; Cellulose; Curcumin; Cyclin D1; Drug Carriers; Drug Liberation; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Humans; Hydrogels; MCF-7 Cells; Melanocytes; Membranes, Artificial; Models, Molecular; Molecular Docking Simulation; Nanoparticles; Polyvinyl Alcohol; Protein Conformation; Spectroscopy, Fourier Transform Infrared; Wound Healing; X-Ray Diffraction

Breast cancer is one of the most lethal types of cancer in women. Curcumin showed therapeutic potential against breast cancer, but applying that by itself does not lead to the associated health benefits due to its poor bioavailability, which appears to be primarily due to poor absorption, rapid metabolism, and rapid elimination. Moreover, poor water solubility of curcumin causes accumulation of a high concentration of curcumin and so decrease its permeability to the cell. Many strategies are employed to reduce curcumin metabolism such as adjuvants and designing novel delivery systems. Therefore, in this study sodium alginate and chitosan were used to synthesize the hydrogels that are known as biocompatible, hydrophilic and low toxic drug delivery systems. Also, folic acid was used to link to chitosan in order to actively targetfolate receptors on the cells.. Chitosan-β-cyclodextrin-TPP-Folic acid/alginate nanoparticles were synthesized and then curcumin was loaded on them. Interaction between the constituents of the particles was characterized by FTIR spectroscopy. Morphological structures of samples were studied by FE-SEM. Release profile of curcumin was determined by dialysis membrane. The cytotoxic test was done on the Kerman male breast cancer (KMBC-10) cell line by using MTT assay. The viability of cells was detected by fluorescent staining. Gene expression was investigated by real-time PCR.. The encapsulation of curcumin into nano-particles showed an almost spherical shape and an average particle size of 155 nm. In vitro cytotoxicity investigation was indicated as dose-respond reaction against cancer breast cells after 24 h incubation. On the other hand, in vitro cell uptake study revealed active targeting of CUR-NPs into spheroids. Besides,. Our results showed the potential of NPs as an effective candidate for curcumin delivery to the target tumor spheroids that confirmed the creatable role of folate receptors.

Topics: Alginates; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Chitosan; Curcumin; Female; Fluorescence; Folic Acid; Gene Expression Regulation; Humans; Inhibitory Concentration 50; Male; Nanospheres; Particle Size; Solubility; Spectroscopy, Fourier Transform Infrared; Spheroids, Cellular

Topics: Antineoplastic Agents; Breast Neoplasms; Curcumin; Drug Delivery Systems; Glucosamine; Graphite; Humans; Hydrogen-Ion Concentration; Quantum Dots

Mounting researches continue to support a favorable role for the drug metal complex against cancer progress and metastasis. However, pharmaceutical barriers were encountered when drug metal complexes needed further pre-clinical and clinical evaluations due to their poor aqueous solubility. In this research, liposomes loaded metal ion as nano-scaled reaction vehicles were used to carry out a synthesis reaction between metal ion and curcumin (Cur) to prepare Cur-metal drug liposomal formulations. The unique flower-like conformation of Cur-M liposomes was observed for the first time and dominated in the Cur-M liposomal formulations system by the cryo-transmission electron microscopy. Different metal ions behaved significant differences in formulations' appearance, release profile, cytotoxic effect against various cell lines, pharmacokinetic profiles, biodistribution and antitumor efficiency. Cur-M liposomes presented enhanced cellular uptake and ROS generation effects, thus augmenting the cytotoxicity of Cur. Superior performances of Cur-copper complexes liposomes were observed in improving Cur stability, promoting apoptosis, inhibiting the proliferation and angiogenesis, therefore enhancing therapeutic effect for primary and metastatic breast cancer. Overall, the current work highlights the potentially significant development value of Cur-M liposomes as an injectable agent for cancer treatment, even superior to the commercial agent Doxil.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Coordination Complexes; Curcumin; Drug Carriers; Humans; Liposomes; Tissue Distribution

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Survival; Curcumin; Dose-Response Relationship, Drug; Drug Carriers; Drug Compounding; Drug Liberation; Female; Glycerol; Humans; Kinetics; Malates; Nanoparticles; Particle Size; Polymers; Spectrum Analysis

Tamoxifen resistance remains the major obstacle to the estrogen receptor positive breast cancer endocrine therapy. Placenta-specific 8 (PLAC8) has been implicated in epithelial-mesenchymal transition and tumorigenesis. However, the molecular mechanisms underlying PLAC8 function in the context of tamoxifen resistance are unclear. Curcumin has attracted considerable attention in the last decades. It is isolated from Curcuma longa and has beneficial effects in cancer therapy. We studied this property by using MCF-7 and tamoxifen-resistant breast cancer cells (MCF-7/TAM) cell lines. PLAC8 can regulate MCF-7/TAM cell drug sensitivity through the MAPK/ERK pathway and shows the potential effects of curcumin or as a possible druggable target against tamoxifen failure.

Topics: Animals; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Curcumin; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Female; Gene Expression; Humans; Immunohistochemistry; Mice; Mitogen-Activated Protein Kinases; Models, Biological; Protein Binding; Protein Stability; Proteins; Signal Transduction; Tamoxifen; Ubiquitination

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Proliferation; Curcumin; Cyclohexanones; Female; G2 Phase Cell Cycle Checkpoints; Gene Expression Regulation, Neoplastic; Humans; MCF-7 Cells; MicroRNAs

Over-expression of COX-2 has been linked with various molecular signaling such as carcinogenesis, invasiveness, and malignant tumour metastasis. Besides, the use of celecoxib is also related to lowering the risk of breast cancer. This study therefore designed to explore the synergistic inhibitory effect of the combination of curcumin and celecoxib on the growth of human breast cancer cells.. In our investigation, we treated MDA-MB-231 cancer cells with different concentrations of curcumin and celecoxib. The enzyme-linked immunoassay was used to measure the COX-2 expression levels. MDA-MB-231 growth was examined by MTS cell viability assay, and synergy detection was carried out using combination index approaches. The drug-likeliness of the tested drugs (curcumin and celecoxib) were computed and predicted ADME pharmacokinetic parameters by in silico. Further, we have conducted BOILED-Egg plot and bioavailability radar analysis for the curcumin and celecoxib.. The result of the physicochemical and ADMET/pharmacokinetic properties showed that these two drugs have good oral and optically bioavailable absorption. The present in silico study could offer a reliable theoretical basis for future structural modification of these compounds to treat breast cancer. The in vitro results suggested that curcumin and celecoxib individually inhibited the growth of MDA-MB-231 cells in a dose-dependent manner. The effect was synergistic for MDA-MB-231 cells relative to the two compounds individually. The synergistic growth inhibitory effect was mediated by a mechanism that possibly involves inhibition of the COX-2 pathways.. Our findings show the prominent anti-proliferative effects of celecoxib and/or curcumin on MDA-MB-231 cells, providing a rationale for further detailed preclinical and potential clinical studies of this combination for breast cancer therapy. Further, these computed parameters suggested that curcumin possesses a high tendency to act as an adjuvant drug with celecoxib in the treatment of breast cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Celecoxib; Cell Proliferation; Cell Survival; Curcumin; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Drug Screening Assays, Antitumor; Drug Therapy, Combination; Female; Humans; Tumor Cells, Cultured

The natural bioactive compounds of Curcuma longa, known as curcuminoids, has been shown to exerts anticancer effects to diverse cancer cell line in vitro, including breast cancer cell line. These curcuminoids consist of curcumin (Cur), demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC). Furthermore, there has never been a study to compare the extent of antiproliferative and apoptotic modulation potential between Cur, DMC and BDMC in the breast cancer cell, until now. In the present study, we explore the efficacy among Cur, DMC and BDMC to alters MCF-7 cell viability, which might lead to apoptotic modulation.. This kind of study was performed in vitro whereby the cells were maintained in an appropriate medium and the anticancer effect of curcuminoids (Cur, DMC and BDMC) was measured by using resazurin-based PrestoBlue cell viability assay. Later, MCF-7 breast cancer cells were cultured in 12 wells plate added with different concentrations of Cur, DMC and BDMC for western blotting analysis. Statistical analysis was performed with GraphPad 8, One-way ANOVA and Student's t-test.. The result showed that Cur, DMC and BDMC inhibiting the proliferation of MCF-7 cells. In the concentration dose of 31.25 μg mL-1, the cell viability in cells treated with Cur is 27%, DMC is 31.5% and BDMC is 46%. The IC50 dose of Cur, DMC and BDMC were 25.63, 29.94 and 36.91 μg mL-1.. Cur is more effective in inhibiting proliferation and apoptotic modulation in MCF-7 cells compare to DMC and BDMC. It represents the potential of Cur, DMC and BDMC as adjunctive therapy in treating breast cancer.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Apoptosis Regulatory Proteins; Autophagy; Autophagy-Related Proteins; Breast Neoplasms; Cell Proliferation; Curcuma; Curcumin; Diarylheptanoids; Female; Humans; MCF-7 Cells

The synergism of combination chemotherapy can only be achieved under specific drug ratios. Herein, hyaluronic acid (HA)-functionalized regenerated silk fibroin-based nanoparticles (NPs) were used to concurrently deliver curcumin (CUR) and 5-fluorouracil (5-FU) at various weight ratios (3.3 : 1, 1.6 : 1, 1.1 : 1, 1 : 1, and 1 : 1.2) to breast tumor cells. The generated HA-CUR/5-FU-NPs were found to have desirable particle sizes (around 200 nm), narrow size distributions, and negative zeta potentials (about -26.0 mV). Interestingly, these NPs showed accelerated drug release rates when they were exposed to buffers that mimicked the multi-hallmarks in the tumor microenvironment (pH/hydrogen peroxide/glutathione/hyaluronidase). The surface functionalization of NPs with HA endowed them with in vitro and in vivo breast tumor-targeting properties. Furthermore, we found that the co-loading of CUR and 5-FU in HA-functionalized NPs exhibited obvious synergistic anti-cancer, pro-apoptotic, and anti-migration effects, and the strongest synergism was found at the CUR/5-FU weight ratio of 1 : 1.2. Most importantly, mice experiments revealed that HA-CUR/5-FU-NPs (1 : 1.2) showed a superior anti-cancer activity against metastatic breast cancer compared to the single drug-loaded NPs and non-functionalized CUR/5-FU-NPs (1 : 1.2). Collectively, these results demonstrate that HA-CUR/5-FU-NPs (1 : 1.2) can be exploited as a robust nanococktail for the treatment of breast cancer and its lung metastasis.

Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Curcumin; Drug Delivery Systems; Drug Therapy, Combination; Humans; Mice; Nanoparticles; Tumor Microenvironment

Insensitivity towards anthracycline drugs like doxorubicin poses a significant challenge in the treatment of breast cancer. Among several factors, Aurora A (a mitotic serine threonine kinase) plays crucial roles in acquiring non-responsiveness towards doxorubicin. However, the mechanisms underlying need to be elucidated. The present study was therefore designed to evaluate the underlying mechanisms of Aurora A mediated doxorubicin insensitivity in MCF-7Dox/R, an isolated resistant-subline of MCF-7 (breast adenocarcinoma cell line). Effect of curcumin, a natural phytochemical in restoring doxorubicin sensitivity by targeting Aurora A was assessed furthermore.. A doxorubicin resistant subline (MCF-7Dox/R) was isolated from the parental MCF-7 cells by treating the cell with gradual step-wise increasing concentration of the drug. Expressions of Aurora A and its target proteins (Akt, IκBα and NFκB) were assessed in both parental and MCF-7Dox/R cells. Both the cell lines were pretreated with curcumin prior to doxorubicin treatment. Cellular proliferation rate was measured using BrdU (5-bromo-2'-deoxyuridine) assay kit. Intracellular doxorubicin accumulation was estimated spectrofluorimetrically. Cellular uptake of curcumin (spectrophotometric and spectrofluorimetric method) and its nuclear localization was confirmed by confocal microscopic study. Protein expressions were determined by western blot analysis. Localization of Aurora A was ascertained by immunofluorescence assay. To explore the possible outcome of impact of curcumin on Aurora A, cell-cycle distribution and apoptosis were performed subsequently.. Higher expressions of Aurora A in MCF-7Dox/R cells led to phosphorylation of Akt as well as IκBα. Phosphorylated IκBα preceded release of NFκB. Phospho-Akt, NFκB consequentially decreased doxorubicin accumulation by enhancing the expressions of ABCG2 and Pgp1 respectively. Curcumin by regulating Aurora A and its target molecules sensitized resistant subline towards doxorubicin mediated G2/M-arrest and apoptosis.. Molecular targeting of Aurora A by curcumin restores chemosensitivity by increasing the efficacy of doxorubicin in breast cancer.
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Topics: Adenocarcinoma; Antineoplastic Agents; Aurora Kinase A; Breast Neoplasms; Curcumin; Doxorubicin; Drug Resistance, Neoplasm; Humans; MCF-7 Cells; NF-kappa B; NF-KappaB Inhibitor alpha; Proto-Oncogene Proteins c-akt; Signal Transduction

C1, a synthetic analog of curcumin, has been reported to show potent antiproliferative effects against a variety of cancer cells. Here, we report a strong anticancer activity of the folate receptor-targeted lipid nanoparticle formulation of C1 against cancer cells and cancer stem cells both in 2D culture and 3D spheroids. The size of the C1 encapsulated folic acid functionalized nanoliposomes (Lipos-C1) was determined to be 83 ± 17 nm. Lipos-C1 nanoparticles displayed sustained C1 release kinetics at both pH 7.4 and 5.5. The folate receptor (FR) targeted nanoliposomes were internalized into FR-positive KB cells via the folate receptor-mediated endocytosis process. Lipos-C1 killed KB cells much more efficiently than C1. Lipos-C1 depolymerized microtubules, generated ROS, caused DNA damage, and induced apoptosis in KB cells. Importantly, Lipos-C1 strongly inhibited the growth of the 3D KB spheroids than C1. Interestingly, Lipos-C1 also suppressed cancer stem cells (CSCs) enriched MCF-7 mammosphere growth by impeding breast cancer stem cells (BCSCs) enrichment, growth, and proliferation. The results suggested that Lipos-C1 could be a promising nanoformulation for cancer chemotherapy.

Topics: Apoptosis; Breast Neoplasms; Cell Line, Tumor; Curcumin; Female; Folic Acid; Humans; MCF-7 Cells; Nanoparticles; Neoplastic Stem Cells

In this study, integrin-mediated targeting and near-infrared fluorescence (NIRF) traceable polyethylene glycol-b-poly(lactic-co-glycolic acid) (PEG-PLGA)-based polymeric nanoparticles (NPs) were prepared to investigate the effects of paclitaxel (PTX) and curcumin (CUR) combination therapy on breast cancer. Cyclic (arginine-glycine-aspartic acid-phenylalanine-lysine) (cRGDfK) was selected as a ligand for breast cancer and conjugated to the end of NPs (cRGDfK-NPs). For fluorescence imaging, sulfo-cyanine 5.5 (Cy5.5) was incorporated into NPs (Cy5.5-NPs). A series of hybrid NPs consisting of NPs, cRGDfK-NPs, and Cy5.5-NPs with drugs encapsulated inside the core (Cy5.5-cRGDfK-NPs/PTX + CUR) were prepared by self-assembly. The efficacy of PTX and CUR combination and the ability of the integrin-mediated targeting of NPs were systemically investigated using a 4T1 mouse breast cancer cell line and a nude mouse xenograft model. We suggested that Cy5.5-cRGDfK-NPs/PTX + CUR has superior theranostic potential against breast carcinoma.

Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Curcumin; Humans; Mice; Nanoparticles; Paclitaxel; Polyethylene Glycols; Precision Medicine

Despite developments in surgery and chemotherapy, effective treatment of breast cancer is still an urgent problem owing to recurrence and metastasis. By combining the advantages of curcumin (Cur), zeolitic imidazolate framework-8 nanoparticles (ZIF-8), and hyaluronic acid (HA) in breast cancer therapy, Cur-loaded and HA-coated ZIF-8 (Cur@ZIF-8@HA) were synthesized using a method based on the pH-dependent solubility of Cur and the electrostatic interactions between zinc ions and carboxyl groups of HA. Cur@ZIF-8 were also prepared as a control group. Comprehensive comparisons of the physicochemical properties and anticancer activities of Cur@ZIF-8@HA and Cur@ZIF-8 were conducted. The results indicated that the degradation of Cur during the synthesis of Cur@ZIF-8 was negligible. The obtained Cur@ZIF-8 and Cur@ZIF-8@HA were truncated cubes with hydrodynamic diameters of 174 and 217 nm, respectively. Cur@ZIF-8@HA possessed better stability during storage in different media, a slower drug release rate under neutral and acidic conditions, and a greater inhibitory effect on breast cancer than Cur@ZIF-8. For 4T1 cells, treatment using Cur@ZIF-8@HA induced more cellular uptake and higher cytotoxicity, accompanied by higher lactate dehydrogenase release, cell cycle arrest in G2/M and S phases, production of reactive oxygen species, and apoptosis. In 4T1 tumor-bearing mice models, Cur@ZIF-8@HA showed a stronger inhibitory effect on tumor growth and pulmonary metastasis. Therefore, Cur@ZIF-8@HA might hold great potential as an agent for the effective therapy of breast cancer.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Curcumin; Drug Carriers; Female; Humans; Hyaluronic Acid; Mice; Nanoparticles

The sustainable cellular delivery of the pleiotropic drug curcumin encounters drawbacks related to its fast autoxidation at the physiological pH, cytotoxicity of delivery vehicles and poor cellular uptake. A biomaterial compatible with curcumin and with the appropriate structure to allow the correct curcumin encapsulation considering its poor solubility in water, while maintaining its stability for a safe release was developed. In this work, the biomaterial developed started by the preparation of an oil-in-water nanoemulsion using with a cytocompatible copolymer (Pluronic F 127) coated with a positively charged protein (gelatin), designed as G-Cur-NE, to mitigate the cytotoxicity issue of curcumin. These G-Cur-NE showed excellent capacity to stabilize curcumin, to increase its bio-accessibility, while allowing to arrest its autoxidation during its successful application as an anticancer agent proved by the disintegration of MDA-MB-231 breast cancer cells as a proof of concept.

Topics: Animals; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cell Line, Tumor; Curcumin; Drug Carriers; Drug Delivery Systems; Drug Stability; Emulsions; Female; Fibroblasts; Gelatin; Humans; Mice; Nanostructures; Olive Oil; Poloxamer; Water

BRCA mutation, one of the most common types of mutations in breast and ovarian cancer, has been suggested to be synthetically lethal with depletion of RAD52. Pharmacologically inhibiting RAD52 specifically eradicates BRCA-deficient cancer cells. In this study, we demonstrated that curcumin, a plant polyphenol, sensitizes BRCA2-deficient cells to CPT-11 by impairing RAD52 recombinase in MCF7 cells. More specifically, in MCF7-siBRCA2 cells, curcumin reduced homologous recombination, resulting in tumor growth suppression. Furthermore, a BRCA2-deficient cell line, Capan1, became resistant to CPT-11 when BRCA2 was reintroduced. In vivo, xenograft model studies showed that curcumin combined with CPT-11 reduced the growth of BRCA2-knockout MCF7 tumors but not MCF7 tumors. In conclusion, our data indicate that curcumin, which has RAD52 inhibitor activity, is a promising candidate for sensitizing BRCA2-deficient cells to DNA damage-based cancer therapies.

Topics: Animals; Antineoplastic Agents; Apoptosis; BRCA2 Protein; Breast Neoplasms; Cell Proliferation; Curcumin; DNA Damage; DNA Repair; Female; Gene Expression Regulation, Neoplastic; Homologous Recombination; Humans; Irinotecan; Mice; Mice, Nude; Mutation; Rad52 DNA Repair and Recombination Protein; Topoisomerase I Inhibitors; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Breast cancer is the most common cancer of women, and fifth leading cause of mortality worldwide. Existing breast cancer regimens are costly and produce severe side effects. This highlights a need for the development of efficient novel therapies, which are cost effective and limit side effects. An electrical pulse (EP)-based chemo therapy, known as electrochemotherapy (ECT) using the natural compound curcumin could be an effective alternative. ECT is a non-surgical modality, which produces excellent anti-tumor efficacy at small drug concentrations due to increased uptake of drugs. In clinics, ECT is shown to be effective in treating advanced, recurrent, and metastatic breast cancers, which are refractory to multiple modalities. ECT with curcumin triggers apoptotic cell death in breast cancer cells and could be an effective alternative, due to curcumin's low cost and reduced side-effects. However, there is a lack of studies quantifying the uptake of curcumin in response to EP application. Towards this, we determined the uptake of different curcuminoids (curcumin, desmethoxycurcumin, and bisdemethoxycurcumin) upon EP application and their impact on cell cytotoxicity. Additionally, we studied the combined effect of calcium chloride (CaCl

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Curcumin; Electricity; Humans; Intracellular Space

We developed here stimuli responsive curcumin loaded microgels based on Pluronic F-127. These microgels were prepared using coupling reaction between the amine modified Pluronic and EDTA. The microgel exhibited the affinity for hydrophobic drug, curcumin and showed pH as well as temperature-dependent release. Furthermore, the cytotoxicity study demonstrated dose-dependent inhibition of MDA-MB-231 cell growth with the most effective IC

Topics: Breast Neoplasms; Curcumin; Delayed-Action Preparations; Female; Humans; MCF-7 Cells; Microgels; Poloxamer

Curcumin is a potential candidate in cancer therapy due to its ability to inhibit many signalling pathways at the same time of exposure because of its unique content of aromatic ring, B diketone, olefinic linker, and O methoxy phenolic groups. Its applications in biomedical therapy is limited because of its sensitivity, and its rapid degradation. In the current study, curcumin inserted into polyelectrolyte pairs (protamine and dextran) and then was functionalized by folic acid conjugated chitosan used for the first time, as theranostic system. Such this strategy allows to improve its mucoadhesion and penetration that increases their accumulation inside cancer cells. CUR-LbL NPs were then used to investigate drug release inside Human Mammary Carcinoma (MCF-7 cell lines) after their incubations for 3 h, 6 h and 24 h. Flow cytometry indicated that the percentages of apoptosis, necrosis and cell cycle arrest were increased significantly in MCF-7 cell lines treated by CUR-LbL NPs. Furthermore, SEM image showed many debris in the section of MCF-7 treated by CUR-LbL NPs. Here, it can be summarized that curcumin functionalized by multi-layered polyelectrolyte capsules can be used as a model to study the fate of the adsorbed nanocarriers and to investigate the drug release inside cells.

Topics: Adhesiveness; Adsorption; Apoptosis; Breast Neoplasms; Cell Cycle Checkpoints; Cell Death; Cell Shape; Chitosan; Curcumin; Drug Compounding; Drug Delivery Systems; Drug Liberation; Female; Folic Acid; Humans; Hydrogen-Ion Concentration; MCF-7 Cells; Nanoparticles; Necrosis; Neoplasm Invasiveness; Spectrophotometry, Ultraviolet; Spectroscopy, Fourier Transform Infrared; Static Electricity; Stereoisomerism; Theranostic Nanomedicine

Targeted delivery and controlled release of drugs are attractive methods for avoiding the drug's leakage during blood circulation and burst release of the drug. We prepared a nano cellulose-based drug delivery system (DDS) for the effective delivery of curcumin (CUR). In the present scenario, the role of nanoparticles in fabricating the DDS is an important one and was characterized using various techniques. The drug loading capacity was high as 89.2% at pH = 8.0, and also the maximum drug release takes place at pH = 5.5. In vitro cell viability studies of DDS on MDA MB-231; breast cancer cells demonstrated its cytotoxicity towards cancer cells. The prepared DDS was also examined for apoptosis, hemocompatibility, and Chorioallantoic membrane (CAM) studies to assess its pharmaceutical field application and the investigation results recommended that it may serve as a potential device for targeted delivery and controlled release of CUR for cancer treatment.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Survival; Cellulose; Cerium; Chick Embryo; Cross-Linking Reagents; Curcumin; Delayed-Action Preparations; Drug Carriers; Drug Compounding; Drug Liberation; Epoxy Compounds; Female; Folic Acid; Humans; Hydrogen-Ion Concentration; Methacrylates; Nanoparticles; Sulfates

Nano drug delivery has been recently used to enhance the stability and bioavailability of chemotherapeutic agents. In this study, Chitosan/protamine nanocarrier was synthesized and used to encapsulate curcumin (CUR). The physicochemical properties of the empty carrier (CHPNPs) and curcumin-containing carrier (CU-CHPNPs) were characterized by TEM imaging, Zetasizer, and FT-IR spectroscopy. The antitumor activity of the prepared nanoparticles was assessed by determination of cell count, cell viability, the level of NF-κB, IL-6, and TNF-α and Bcl-2 gene expression in breast cancer cells (MCF-7). The results revealed that the obtained CU-CHPNPs had an average hydrodynamic size of 200 nm, zeta potential of +26.66 mv, and showed a drug encapsulation efficiency of 67%, and drug loading capacity of 40.20%. The cell-based assay showed a significant reduction in the cell viability, and NF-κB, TNF-α, and IL-6 levels upon treatment with CU-CHPNPs as compared to free CUR. Finally, the (CU-CHPNPs) downregulated the expression of the Bcl-2 anti-apoptotic gene more effectively than CUR and the CHPNPs comparing with the β Actin housekeeping gene. This study concluded that the nano-encapsulation of CUR significantly enhances its antitumor efficacy via inhibition of NF-κB, IL-6, and TNF-α and downregulation of Bcl-2.

Topics: Antineoplastic Agents; Breast Neoplasms; Chitosan; Curcumin; Cytokines; Drug Carriers; Female; Gene Expression; Humans; Nanoparticles; NF-kappa B; Protamines; Spectroscopy, Fourier Transform Infrared

Topics: Breast Neoplasms; Click Chemistry; Curcumin; Drug Carriers; Folic Acid; Metal-Organic Frameworks; Molecular Targeted Therapy

Topics: Breast Neoplasms; Cell Line, Tumor; Curcumin; Drug Carriers; Female; Glycols; Humans; Nanoparticles; Particle Size; Polylactic Acid-Polyglycolic Acid Copolymer

Chemoresistance (CR) is one of the reasons why chemotherapy agents like Gemcitabine (GMC) remain insufficient in healing breast cancer. Activation of Nuclear Factor-kappa B (NF-κB) during chemotherapy is known as an important factor in the development of CR. The hydrophobic polyphenol curcumin is shown to inhibit NF-κB and hence CR. The aim of this work was to increase the poor bioavailability of curcumin by loading it into the nano-micelles made of Poly (Lactide-co-Glycolide) (PLGA) and levan, where levan as a natural fructose homopolymer makes the nano-micelle more stable and increases its uptake using the fructose moieties. In this study, a PLGA-levan-curcumin formulation (PLC) was designed and characterized. The size was measured as 154.16 ± 1.45 nm with a 67.68% encapsulation efficiency (EE%). The incorporation between the components was approved. Levan made the nano-micelles stable for at least three months, increased their uptake, and led to a 10,000-fold increase in the solubility of curcumin. The enhanced bioavailability of curcumin reduced the NF-κB levels elevated by GMC, both in vitro and in vivo. The PLC showed a complete tumor treatment, while GMC only showed a rate of 52%. These point to the great potential of the PLC to be used simultaneously with chemotherapy.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Biological Availability; Breast Neoplasms; Calorimetry, Differential Scanning; Cell Death; Curcumin; Drug Compounding; Dynamic Light Scattering; Female; Fluorescence; Fructans; Humans; MCF-7 Cells; Micelles; Nanoparticles; NF-kappa B; Particle Size; Polylactic Acid-Polyglycolic Acid Copolymer; Rats; Spectroscopy, Fourier Transform Infrared; Static Electricity

Curcumin is a natural phytochemical with potent anti-neoplastic properties including modulation of p53. Targeting p53 activity has been suggested as an important strategy in cancer therapy. The purpose of this study was to describe a mechanism by which curcumin restores p53 levels in human cancer cell lines. HeLa, SiHa, CaSki and MDA-MB-231 cells were exposed to curcumin and a pulse and chase and immunoprecipitation assays were performed. Here we showed that curcumin increases the half-life of p53 by a physical interaction between p53-NQO1 (p53 - NAD(P)H:quinone oxidoreductase 1) proteins after treatment with curcumin. Interestingly, the cell viability assay after treatment with curcumin showed that the cytotoxic activity was selectively higher in cervical cancer cells contained wild type p53 but not in breast cancer cells contained mutated p53. The cytotoxic effect of curcumin in cervical cancer cells was related to the complex p53-NQO1 that avoids the interaction between p53 and its negative regulator ubiquitin ligase E6-associated protein (E6AP). Finally, we demonstrated that in pancreatic epithelioid carcinoma cells (PANC1) that are knockout for NQO1, the reestablishment of NQO1 expression can stabilize p53 in presence of curcumin. Collectively, our findings showed that curcumin is necessary to promote the protein interaction of NQO1 with p53, therefore, it increases the half-life of p53, and permits the cytotoxic effect of curcumin in cancer cells containing wild type p53. Our findings suggest that the use of curcumin may reactivate the p53 pathway in cancer cells with p53 wild-type.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; Female; Gene Expression Regulation, Neoplastic; Half-Life; HeLa Cells; Humans; NAD(P)H Dehydrogenase (Quinone); Protein Binding; Protein Stability; Tumor Suppressor Protein p53; Up-Regulation; Uterine Cervical Neoplasms

Breast cancer is a worldwide commonly found malignancy in women and effective treatment is regarded as a huge clinical challenge even in the presence of several treatment options. Extensive literature is available demonstrating polyphenols as phytopharmaceutical anticancer agents. Among the polyphenols, quercetin and curcumin have been reported to have a strong potential against breast cancer. However, so far, no comprehensive study has been performed to demonstrate the anticarcinogenic effects of curcumin, quercetin, and their combinations with somatostatin on the fatty acid profile of breast cancer cell membranes. We used MCF-7 and MDA-MB231 breast cancer cells incubated with curcumin and quercetin for 24 h, in the absence and presence of somatostatin, at their EC

Topics: Antineoplastic Agents; Antioxidants; Biomarkers, Tumor; Breast Neoplasms; Cell Membrane; Curcumin; Fatty Acids; Female; Gene Expression Regulation, Neoplastic; Hormones; Humans; Quercetin; Somatostatin; Tumor Cells, Cultured

Treatment of breast cancer by paclitaxel (PAX) often encounters therapeutic failure most likely caused by innate/acquired resistance. Cancer stem cells (CSCs) and multidrug resistance complex (MDR-1 or P-glycoprotein) overexpression are main mechanisms implicated in chemoresistance. Increased aldehyde dehrogenase-1 (ALDH-1) was previously correlated with the stemness features of CSCs and hence is used as a marker for identification and CSCs targeting. The present study, therefore, aimed at investigating the effect of both curcumin (CUR) and vitamin D3 (D3) on MDR-1 and ALDH-1 expression and consequently the resistance to PAX both in vitro and in vivo. CUR was isolated from Turmeric rhizomes and identified using UPLC-ESI-MS/MS. For in vitro studies, the antiproliferative effect of PAX, CUR, 1,25(OH)2D3 (the active form of D3, also known as calcitriol) was determined, each alone and combined (PAX+CUR, PAX+1,25(OH)2D3, and PAX+CUR+1,25(OH)2D3) on MCF-7 breast cancer cells. Ehrlich ascites carcinoma solid tumor animal model was also used for in vivo studies. Combining CUR and/or 1,25(OH)2D3 to PAX showed synergistic cytotoxic interaction on MCF-7 cells. The apoptotic potential was also enhanced, as evidenced by a significant increase in caspase-7 and -9 as well as the pro-apoptotic Bax whereas a decrease in Bcl-2 levels was reported. Combining CUR and 1,25(OH)2D3 to PAX caused a downregulation in both MDR-1 and ALDH-1 gene expression in MCF-7 besides a decrease in their protein levels. In vivo, the triple therapy group (PAX+CUR+D3) showed the least tumor size. It also showed the lowest levels of MDR-1 and ALDH-1. PAX alone, however, showed increased levels of MDR-1 and ALDH-1 compared to control. Overall, the present study showed that PAX, as a monotherapy, demonstrated acquired resistance possibly by increasing MDR-1 expression and enriching CSCs population, as evidenced by increased ALDH-1. However, using CUR and D3 enhanced tumor response to PAX.

Topics: Aldehyde Dehydrogenase 1 Family; Animals; Apoptosis; ATP Binding Cassette Transporter, Subfamily B, Member 1; Breast Neoplasms; Cholecalciferol; Curcumin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Humans; MCF-7 Cells; Mice; Paclitaxel; Receptors, Calcitriol; Retinal Dehydrogenase

Due to its high therapeutic efficiency and low systemic toxicity, natural bioactive curcumin has attracted more and more attention as a potential antineoplastic drug. Although the emergence of a carrier-free nanocrystalline technology could improve the solubility and guarantee the high drug loading of curcumin, uncontrollable drug release and fast systemic metabolism are definite obstacles that hinder its further application in cancer treatment. Here, hyaluronic acid (HA) modification was carried out on the surface of curcumin nanocrystals (Cur-NC) to obtain surface reformed hydrophilic HA@Cur-NCs that exhibit prolonged biodistribution. Besides this, HA@Cur-NC shows enhanced intracellular uptake in CD44 overexpressing MDA-MB-231 cells, but reduced uptake when pre-treated with HA. The apoptotic effects, confirmed by flow cytometry, suggest that HA@Cur-NC could achieve high anticancer activity against MDA-MB-231 cells. In vivo pharmacokinetic studies suggest that the t

Topics: Animals; Breast Neoplasms; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Survival; Curcumin; Drug Carriers; Drug Liberation; Female; Half-Life; Hemolysis; Humans; Hyaluronic Acid; Hydrophobic and Hydrophilic Interactions; Mice; Mice, Inbred BALB C; Nanoparticles; Rats; Rats, Sprague-Dawley; Tissue Distribution

Cancer stem cell like cells (CSCs) present a challenge in the management of cancers due to their involvement in the development of resistance against various chemotherapeutic agents. Over expression of ABCG2 transporter gene is one of the factors responsible for drug resistance in CSCs, which causes efflux of therapeutic drugs from these cells. The development of inhibitors against CSCs has not achieved any significant success, till date. In this work, we have evaluated the anti-proliferative activity of curcumin (Cur) and quinacrine (QC) against CSCs using in vitro model system. Cur and QC synergistically inhibited the proliferation, migration and invasion of CSCs enriched side population (SP) cells of cigarette smoke condensate induced breast epithelial transformed (MCF-10A-Tr) generated metastatic cells. Cur + QC combination increased the DNA damage and inhibited the DNA repair pathways in SP cells. Uptake of QC increased in Cur pre-treated SP cells and this combination inhibited the ABCG2 activity by the reduction of ATP hydrolysis in cells. In vitro DNA binding reconstitution system suggests that QC specifically binds to DNA and caused DNA damage inside the cell. Decreased level of ABCG2, representative cell survival and DNA repair proteins were noted after Cur + QC treatment in SP cells. The molecular docking studies were performed to examine the binding behaviour of these drugs with ABCG2, which showed that QC (-53.99 kcal/mol) and Cur (-45.90 kcal/mol) occupy a highly overlapping interaction domain. This suggested that in Cur pre-treated cells, the Cur occupied the ligand-binding site in ABCG2, thus making the ligand binding site unavailable for the QC. This causes an increase in the intracellular concentration of QC. The results indicate that Cur + QC combination causes CSCs death by increasing the concentration of QC in the cells and thus causing the DNA damage and inhibiting the DNA repair pathways through modulating the ABCG2 activity.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; ATP Binding Cassette Transporter, Subfamily G, Member 2; Breast Neoplasms; Cell Line, Tumor; Curcumin; DNA Damage; DNA Repair; DNA, Neoplasm; Drug Synergism; Female; Humans; Neoplasm Proteins; Neoplastic Stem Cells; Quinacrine

We previously reported the potential of aminonaphthoquinone derivatives as therapeutic agents against breast and other oestrogen-responsive tumours when combined with curcumin. This study aimed at screening of novel aminonaphthoquinone derivatives (Rau 008, Rau 010, Rau 015 and Rau 018) combined with curcumin for cytotoxic, anti-angiogenic and anti-metastatic effects on MCF-7 and MDA-MB-231 breast cancer cells.. Cytotoxic and anti-angiogenic effects were analysed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and enzyme-linked immunosorbent assay; while anti-metastatic effects were measured using adhesion assay, Boyden chambers and Matrigel.. Curcumin combined with Rau 008 elicited marked cytotoxic effects in MCF-7 cells compared with the individual treatments, whereas when it was combined with Rau 015 and with Rau 018, it displayed similar effects in MDA-MB-231 cells. The anti-angiogenic effect of Rau 015 plus curcumin in MCF-7 cells and Rau 018 plus curcumin in MDA-MB-231 cells was more effective than individual treatments, while the metastatic capability of MDA-MB-231 cells was significantly reduced after treatment with the aminonaphthoquinone-curcumin combinations.. Aminonaphthoquinones may offer significant promise as therapeutic agents against breast cancer, particularly when combined with curcumin.

Topics: Breast Neoplasms; Cell Adhesion; Cell Movement; Cell Survival; Curcumin; Disease Progression; Extracellular Matrix; Female; Humans; MCF-7 Cells; Naphthoquinones; Neoplasm Invasiveness; Neovascularization, Pathologic; Vascular Endothelial Growth Factor A

Current conventional mono and combination therapeutic strategies often fail to target breast cancer tissue effectively due to tumor heterogeneity comprising cancer stem cells (CSCs) and bulk tumor cells. This is further associated with drug toxicity and resistivity in the long run. A nanomedicine platform incorporating combination anti-cancer treatment might overcome these challenges and generate synergistic anti-cancer effects and also reduce drug toxicity. GANT61 and curcumin were co-delivered via polymeric nanoparticles (NPs) for the first time to elicit enhanced anti-tumor activity against heterogeneous breast cancer cell line MCF-7. We adopted the single-emulsion-solvent evaporation method for the preparation of the therapeutic NPs. The GANT61-curcumin PLGA NPs were characterized for their size, shape and chemical properties, and anti-cancer cell studies were undertaken for the plausible explanation of our hypothesis. The synthesized GANT61-curcumin PLGA NPs had a spherical, smooth surface morphology, and an average size of 347.4 d. nm. The NPs induced cytotoxic effects in breast cancer cells at a mid-minimal dosage followed by cell death via autophagy and apoptosis, reduction in their target protein expression along with compromising the self-renewal property of CSCs as revealed by their in vitro cell studies. The dual-drug NPs thus provide a novel perspective on aiding existing anti-cancer nanomedicine therapies to target a heterogeneous tumor mass effectively.

Topics: Adenocarcinoma; Animals; Apoptosis; Autophagy; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; Drug Liberation; Endocytosis; Female; Humans; MCF-7 Cells; Mice; Nanoparticles; Particle Size; Phosphatidylinositol 3-Kinases; Photoelectron Spectroscopy; Polylactic Acid-Polyglycolic Acid Copolymer; Proto-Oncogene Proteins c-akt; Pyridines; Pyrimidines; Spectroscopy, Fourier Transform Infrared; Spheroids, Cellular; Static Electricity; Zinc Finger Protein GLI1

Curcumin (CUR), an antioxidant with p-glycoprotein inhibiting activity may be encapsulated with gemcitabine (GEM) as nanosuspension to enhance its anticancer potentiality synergistically.. Folate conjugated single (CUR/GEM) and dual (CUR + GEM) drug-loaded nanoformulations were prepared and evaluated for P-glycoprotein-1 (pgy-1) gene resistance, followed by in vitro cellular uptake and cytotoxicity assay in cells. The in vivo biodistribution and scintigraphic imaging was done after radiolabeling the nanoparticles with. The folate conjugated dual drug formulations (FCGNPs) gave better results in suppressing the pgy-1 gene and also showed higher cellular uptake, cytotoxicity, apoptosis, and cell cycle arrest. The radiolabeled nanoformulations were highly stable and FCGNPs showed higher accumulation in the MDA-MB-231 tumor region than folate unconjugated dual drug NPs (CGNPs) as evidenced by scintigraphic imaging and biodistribution studies. The in vivo therapeutic efficacy of FCGNPs was higher compared to unconjugated and respective single-drug formulations.. Two drugs in one platform lower breast adenocarcinoma by lowering drug resistance and improving cytotoxic effects.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Curcumin; Deoxycytidine; Drug Carriers; Drug Delivery Systems; Female; Folic Acid; Gemcitabine; Humans; Mice, Nude; Nanoparticles; Polylactic Acid-Polyglycolic Acid Copolymer

Combination of natural agents has received a great attention in cancer treatment because of synergistically increased apoptotic effect on cancer cell lines by triggering several apoptotic signaling pathways. However, the hydrophobic nature, poor bioavailability and low cellular uptake of most natural agents limit their therapeutic effectiveness. The purpose of this study was to design Apoferritin nanoparticles loaded with Quercetin and Curcumin (Que-Cur-HoS-Apo NPs) and to test their synergistic antitumor properties on a breast cancer cell line (MCF7). The physico-chemical characterization of the Que-Cur-HoS-Apo NPs by Size Exclusion Chromatography (FPLC) and Dynamic Light Scattering (DLS) confirmed the encapsulation of the compounds in the protein cage with narrow size distribution in the range 17.4 ± 1.2 nm. Cell viability study indicated that Que-Cur-HoS-Apo NPs were able to exert a more pronounced effect at lower dose on the MCF7 cell line when compared to the free combination of the drugs. The Que-Cur-HoS-Apo system allowed cellular uptake of natural agents thus triggering enhanced apoptosis. These effects were confirmed by Annexin-V/7-AAD Staining Assay and intracellular Reactive Oxygen Species (ROS) quantitative detection. These results suggest the potential of Que-Cur-HoS-Apo NPs as a promising anti-cancer agent in breast cancer therapy and pave the way to examine Que-Cur-HoS-Apo NPs effect in vivo.

Topics: Animals; Antineoplastic Agents; Antioxidants; Apoferritins; Apoptosis; Breast Neoplasms; Cell Survival; Curcumin; Drug Delivery Systems; Drug Synergism; Drug Therapy, Combination; Female; Horses; Humans; MCF-7 Cells; Nanoparticles; Quercetin; Reactive Oxygen Species; Spleen

Topics: Bacteria; Breast Neoplasms; Colonic Neoplasms; Curcumin; HEK293 Cells; Humans; MCF-7 Cells; Nanoparticles; Quantum Dots; Spectroscopy, Fourier Transform Infrared

Chemotherapy is an important method for treating breast cancer. However, multidrug resistance is one of the major challenges in breast cancer chemotherapy. There is an urgent need to develop novel, effective antitumor strategies that will perfect existing therapeutic regimens. In this study, the double-targeted nanocarrier, Quercetin-3'3-dithiodipropionic acid-Astragalus polysaccharides-Folic acid (QDAF), was successfully synthesized and self-assembled into a neoteric nano-targeted delivery strategy, named nano-pomegranates, and which were utilized to effectively inhibit multidrug resistance in estrogen receptor α (ERα)-positive breast tumor. The outstanding abilities of nano-pomegranates to release the drug in a reducing environment was determined by in vitro release assay. The cellular studies in MCF-7 cells were examined that nano-pomegranates have remarkable efficiencies of enhancing cellular uptake, inhibition and necrosis and apoptosis.

Topics: Animals; Astragalus Plant; Breast Neoplasms; Curcumin; Drug Carriers; Drug Delivery Systems; Drug Liberation; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Estrogen Receptor alpha; Female; Folic Acid; Humans; MCF-7 Cells; Mice, Nude; Nanoparticles; Polysaccharides; Quercetin; Xenograft Model Antitumor Assays

Current anticancer drugs exhibit limited efficacy and initiate severe side effects. As such, identifying bioactive anticancer agents that can surpass these limitations is a necessity. One such agent, curcumin, is a polyphenolic compound derived from turmeric, and has been widely investigated for its potential anti-inflammatory and anticancer effects over the last 40 years. However, the poor bioavailability of curcumin, caused by its low absorption, limits its clinical use. In order to solve this issue, in this study, curcumin was encapsulated in chitosan-coated nanoliposomes derived from three natural lecithin sources. Liposomal formulations were all in the nanometric scale (around 120 nm) and negatively charged (around -40 mV). Among the three lecithins, salmon lecithin presented the highest growth-inhibitory effect on MCF-7 cells (two times lower growth than the control group for 12 µM of curcumin and four times lower for 20 µM of curcumin). The soya and rapeseed lecithins showed a similar growth-inhibitory effect on the tumor cells. Moreover, coating nanoliposomes with chitosan enabled a higher loading efficiency of curcumin (88% for coated liposomes compared to 65% for the non-coated liposomes) and a stronger growth-inhibitory effect on MCF-7 breast cancer cells.

Topics: Animals; Antineoplastic Agents; Biological Availability; Brassica rapa; Breast Neoplasms; Chitosan; Curcumin; Drug Carriers; Drug Compounding; Drug Delivery Systems; Female; Humans; Lecithins; Liposomes; MCF-7 Cells; Nanoparticles; Salmon; Tumor Cells, Cultured

In this research, programmed death ligand 1 (PDL1) binding peptide was used for targeted delivery of curcumin to high PDL1-expressing breast cancer cells. Human serum albumin-curcumin nanoparticles (HSA/Cur NP) were first prepared by desolvation method and then functionalized with PDL1 binding peptide. Peptide conjugation to HSA/Cur NPs was confirmed by Fourier transform infrared and UV-visible spectroscopy. The formation of HSA/Cur NP was characterized by transmission electron microscope and scanning electron microscope. The size and zeta potential were determined by dynamic light scattering. The average particle size of the HSA/Cur NPs and peptide-HSA/Cur NPs were 197 and 246.5 nm, respectively. Evaluation of cellular uptake showed enhanced internalization of peptide-HSA/Cur NPs in high PDL1-expressing cancer cells compared to HSA/Cur NPs. The cell viability and apoptosis determination demonstrated higher cytotoxicity of HSA/Cur NPs relative to free curcumin in breast cancer cells. Peptide conjugation to HSA/Cur NPs increased cytotoxicity significantly concerning high PDL1-expressing breast cancer cells. In conclusion, peptide-HSA/Cur NPs improved cellular uptake and cytotoxicity of HSA/Cur NPs in high PDL1-expressing breast cancer cells. These results suggest that PDL1 has potential to be used as a target for selective drug delivery and promising candidate for the treatment of PDL1-expressing breast cancer cells.

Topics: Apoptosis; B7-H1 Antigen; Breast Neoplasms; Cell Survival; Curcumin; Female; Humans; MCF-7 Cells; Nanoparticles; Oligopeptides; Protein Binding; Serum Albumin, Human

Emerging cancer therapy requires highly sensitive diagnosis in combination with cancer-targeting therapy. In this study, a self-assembled pH-sensitive curcumin (Cur)-loaded nanoparticle of. The synthesized amphiphilic HA-CHEMS conjugates and TPGS self-assembled into Cur-loaded nanoparticles (HA-CHEMS-Cur-TPGS NPs) in an aqueous environment. The physicochemical properties of HA-CHEMS-Cur-TPGS NPs were characterized by transmission electron microscopy (TEM) and dynamic lighter scattering (DLS). The in vitro cytotoxicity of HA-CHEMS-Cur-TPGS NPs against breast cancer cells was evaluated by using the methyl thiazolyl tetrazolium (MTT) assay. Moreover, the in vivo animal experiments of HA-CHEMS-Cur-TPGS NPs including SPECT/CT imaging biodistribution and antitumor efficiency were investigated in 4T1 tumor-bearing BALB/c mice; furthermore, pharmacokinetics were investigated in healthy mice.. The results indicated that HA-CHEMS-Cur-TPGS NPs with stable

Topics: alpha-Tocopherol; Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Curcumin; Female; Humans; Hyaluronic Acid; Mice, Inbred BALB C; Nanoparticles; Particle Size; Polyethylene Glycols; Proton Magnetic Resonance Spectroscopy; Technetium; Theranostic Nanomedicine; Tissue Distribution

Systemic toxicity caused by conventional chemotherapy is often regarded as one of the major challenges in the treatment of cancer. Over years, the trigger-based modality has gained much attention as it holds the spatiotemporal control over release and internalization of the drug. In this article, we are reporting an increase in the anti-tumor efficacy of curcumin due to ultrasound pulses. MDA MB 231 breast cancer and B16F10 melanoma cells were incubated with lecithin-based curcumin encapsulated nanoemulsions and exposed to ultrasound in the presence and absence of microbubble. Ultrasound induced sonoporation enhanced the cytotoxicity of curcumin in MDA MB 231 and B16F10 cancer cells in the presence of microbubble by 100- and 64-fold, respectively. To study the spatiotemporal delivery of curcumin, we developed B16F10 melanoma subcutaneous tumor on both the flanks of C57BL/6 mice but only the right tumor was exposed to ultrasound. Insonation of the right tumor spatially enhanced the cytotoxicity and enabled the substantial regression of the right tumor compared to the unexposed left tumor which grew continuously in size. This study showed that the ultrasound has the potential to target and increase the drug's throughput to the tumor and enable effective treatment.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Proliferation; Curcumin; Drug Delivery Systems; Female; Humans; Lecithins; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Micelles; Nanotechnology; Rats; Rats, Wistar; Spatio-Temporal Analysis; Tissue Distribution; Tumor Cells, Cultured; Ultrasonography; Xenograft Model Antitumor Assays

Nanogel based drug delivery systems have been broadly used for cancer treatment. In this research, octadecylamine was grafted to chondroitin sulfate using three different mole ratios (10, 20, and 30) and named CS-ODA1, 2, and 3, respectively. The amide bond formation between chondroitin sulfate and octadecylamine was confirmed by 1H-nuclear magnetic resonance (HNMR) in the CS-ODA3 sample; therefore, further analysis was performed on this sample. Curcumin was loaded at defined Cur/CS-ODA ratios (5, 10 and 15%) and CS-ODA3 with 10% curcumin was selected for further experiments due to more entrapment efficiency (79.56% ± 5.56). In vitro release profile of the curcumin loaded nanogels showed >80% release after 70 h. In addition, the results of MTT analysis on the MCF-7 cell line showed almost no toxicity toward blank nanogels, while curcumin-loaded nanogels induced significant death after 24 h. In the end, analysis of the cell cycle using MCF-7 cells also confirmed the cytotoxicity of curcumin loaded nanogels. This study also showed that the presence of curcumin loaded chondroitin sulfate nanogels could successfully increase cellular uptake in comparison with free curcumin. The synthesized nanogels containing curcumin are expected to be effective for further studies in cancer treatment.

Topics: Breast Neoplasms; Chondroitin Sulfates; Curcumin; Drug Delivery Systems; Female; Humans; MCF-7 Cells; Micelles; Nanogels

Chemobrain is one of the problems that may arise during or after treatment and there is currently no specific treatment for this condition. Our case was a 76-year-old female patient who presented to our clinic with complaints of forgetfulness that did not affect daily living activities for the last year. Breast cancer was diagnosed in 2013 and she has been receiving anastrozole treatment for 6 years after local mass excision surgery and radiotherapy. After a comprehensive geriatric evaluation, cognitive impairment due to systemic cancer therapy was detected and treatment was started with Theracurmin 90 mg twice a day therapy. After 3-months of Theracurmin therapy, she had no cognitive improvement during the follow-up. This case report demonstrated that Theracurmin treatment may be a new option for chemobrain.

Topics: Aged; Anastrozole; Antineoplastic Agents, Hormonal; Breast Neoplasms; Cognition; Cognition Disorders; Curcumin; Female; Geriatric Assessment; Humans; Mastectomy, Segmental; Nootropic Agents; Radiotherapy; Treatment Outcome

Her2-dependent breast cancer is treated with pharmacological drugs (eg, Herceptin, lapatinib) that target Her2 signaling. Curcumin has emerged as a potential co-treatment for this and other cancers, but prior studies have focused on non-attainable concentrations. Here we test the hypothesis that attainable in vivo levels of dietary curcumin can reduce Her2 signaling. Consistent with previous studies, higher dose curcumin (18 μmol/L) inhibits Her2-Akt pathway signaling (pHer2, total Her2 and pAkt levels) and cell growth using AU565 human breast cancer cells. We then examined lower, more physiologically relevant concentrations of curcumin, alone and in combination with other dietary botanicals (quercetin and OptiBerry fruit extract). At 4 μmol/L, curcumin reduced Her2 signaling, and even more when combined with quercetin or OptiBerry. At 1.5 μmol/L curcumin, pHer2 and Her2 (but not pAkt) were reduced, with all three pathway markers reduced more in the presence of quercetin. We also found that 1.5 μmol/L curcumin strongly potentiated lapatinib inhibition of Her2-Akt pathway signaling, and more so for pAkt, when combined with quercetin plus OptiBerry (CQO). Parallel analyses revealed cell growth inhibition at 18 and 4 μmol/L but not 1.5 μmol/L curcumin, and potentiation of 1.5 μmol/L curcumin growth arrest with other botanicals +/- lapatinib. These studies demonstrate that a physiological attainable level of curcumin (1.5 μmol/L) can reduce some components of the critical Her2-Akt pathway; that even more complete inhibition can be achieved by combination with other dietary botanicals; and that curcumin and other botanicals can potentiate the action of the Her2-cancer metastatic drug lapatinib, in turn suggesting the potential anti-cancer clinical use of these botanicals.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Curcumin; Female; Humans; Lapatinib; Phytochemicals; Plant Extracts; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Quercetin; Receptor, ErbB-2; Signal Transduction

Topics: Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cell Line, Tumor; Curcumin; Delayed-Action Preparations; Drug Screening Assays, Antitumor; Female; Graphite; Humans; Hydrogen-Ion Concentration; Microspheres; Quantum Dots

Curcumin displays anticancer properties; however, some issues with the drug delivery mode limit its therapeutic use. Although reformulation and derivatization of curcumin have improved its bioavailability, curcumin derivatives may not retain the same anticancer properties as the parent compound. The present study investigated the anticancer properties of two curcumin complexes, the iron‑curcumin [Fe(Cur)3] and boron‑curcumin [B(Cur)2] complexes, in the MDA‑MB‑231 breast cancer cell line. The cellular localization of curcumin, B(Cur)2 and Fe(Cur)3 was determined by fluorescence microscopy. Cell proliferation, migration and invasion were also analysed. Furthermore, apoptosis‑associated proteins were detected by using a proteome profiler array, and ion channel gene expression was analysed by reverse transcription‑quantitative PCR. The results demonstrated that the three compounds were localized in the perinuclear and cytoplasmic regions of the cell, and displayed cytotoxicity with IC50 values of 25, 35 and 8 µM for curcumin, B(Cur)2 and Fe(Cur)3, respectively. In addition, the three compounds inhibited cell invasion, whereas only curcumin and B(Cur)2 inhibited cell migration. Furthermore, cell exposure to curcumin resulted in an increase in the relative expression of the two key proapoptotic proteins, cytochrome c and cleaved caspase‑3, as well as the antiapoptotic protein haem oxygenase‑1. In addition, curcumin increased the expression levels of the voltage‑gated potassium channels Kv2.1 and Kv3.2. Similarly, the expression levels of the chloride channel bestrophin‑1 and the calcium channel coding gene calcium voltage‑gated channel auxiliary subunit γ4 were increased following exposure to curcumin. Taken together, these results indicated that Fe(Cur)3 and B(Cur)2 may display similar anticancer properties as curcumin, suggesting that chemical complexation may be considered as a strategy for improving the potency of curcumin in the treatment of breast cancer.

Topics: Antineoplastic Agents; Apoptosis; Boron Compounds; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Curcumin; Drug Screening Assays, Antitumor; Female; Humans; Iron Compounds

Breast cancer is the leading cause of cancer mortality in women worldwide. Conventional cancer treatment is costly and results in many side effects. Dietary bioactive compounds may be a potential source for breast cancer prevention and treatment. In this scenario, the aim of this study was to investigate the effects of the bioactive compounds resveratrol, curcumin and piperine (R-C-P) on MCF-7 breast cancer cells and to associate them to Glyoxalase 1 (GLO1) activity. The findings indicate that R-C-P exhibits cytotoxicity towards MCF-7 cells. R-C-P decreased mitochondrial membrane potential (ΔΨm) by 1.93-, 2.04- and 1.17-fold, respectively. Glutathione and N-acetylcysteine were able to reverse the cytotoxicity of the assessed bioactive compounds in MCF-7 cells. R-C-P reduced GLO1 activity by 1.36-, 1.92- and 1.31-fold, respectively. R-C-P in the presence of antimycin A led to 1.98-, 1.65- and 2.16-fold decreases in D-lactate levels after 2 h of treatment, respectively. Glyoxal and methylglyoxal presented cytotoxic effects on MCF-7 cells, with IC

Topics: Alkaloids; Benzodioxoles; Breast Neoplasms; Curcumin; Female; Humans; Lactoylglutathione Lyase; MCF-7 Cells; Membrane Potential, Mitochondrial; Piperidines; Polyunsaturated Alkamides; Resveratrol

Multi-drug chemotherapy has been one of the most popular strategies for the treatment of malignant tumors, and has achieved desirable therapeutic outcomes. The objective of the present study is to develop biodegradable PCEC nanoparticles (NPs) for the co-delivery of paclitaxel (PTX) and curcumin (CUR), and investigate the antitumor effect of the drug delivery system (DDS: PTX-CUR-NPs) against breast cancer both in vitro and in vivo. The prepared PTX-CUR-NPs had a small size of 27.97 ± 1.87 nm with a low polydispersity index (PDI, 0.197 ± 0.040). The results exhibited slow release of PTX and CUR from the DDS without any burst effect. Further, the PTX-CUR-NPs displayed a dose-dependent cytotoxicity in MCF-7 cells with a higher apoptosis rate (64.29% ± 1.97%) as compared to that of free drugs (PTX + CUR, 34.21% ± 0.81%). The cellular uptake study revealed that the drug loaded PCEC polymeric nanoparticles were more readily uptaken by tumor cells in vitro. To evaluate the in vivo anti-tumor effect, the PTX-CUR-NPs were intravenously administered to BALB/c nude mouse xenografted with MCF-7 cells and the results exhibited significant inhibition of tumor growth with prolonged survival time and reduced side effect when compared with free drugs (PTX + CUR). Moreover, the administration of PTX-CUR-NPs treatment led to lower Ki67 expression (p < 0.05), and enhanced TUNEL positivity (higher apoptosis, p < 0.01) in tumor cells as compared to other treatment groups, suggesting the therapeutic efficacy of the DDS. Altogether, the present study suggests that the DDS PTX-CUR-NPs could be employed for the effective treatment of breast cancers in near future.

Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Curcumin; Drug Delivery Systems; Female; Humans; Mice; Mice, Inbred BALB C; Nanoparticles; Paclitaxel

Topics: Anti-Bacterial Agents; Breast Neoplasms; Chitosan; Curcumin; Escherichia coli; Female; Humans; Metal Nanoparticles; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Nanostructures; Zinc Oxide

Curcumin is known for its anticancer and migrastatic activity in various cancers, including breast cancer. Newer curcumin derivatives are being explored to overcome limitations of curcumin like low bioavailability, stability, and side effects due to its higher dose. In this study, the synthesis of ST09, a novel curcumin derivative, and its antiproliferative, cytotoxic, and migrastatic properties have been explored both in vitro and in vivo.. After ST09 synthesis, anticancer activity was studied by performing standard cytotoxicity assays namely, lactate dehydrogenase (LDH) release assay, 3-(4, 5-dimethylthiazol-2-yl)-2-5-diphenyletrazolium bromide (MTT), and trypan blue exclusion assay. Annexin-FITC, cell cycle analysis using flow cytometry, and Western blotting were performed to elucidate cell death mechanisms. The effect on the inhibition of cell migration was studied by transwell migration assay. An EAC (Ehrlich Ascites carcinoma) induced mouse tumor model was used to study the effect of ST09 on tumor regression. Drug toxicity was measured using aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN), and flow-cytometry based lymphocyte count. Histological analysis was performed for assessment of any tissue injury post ST09 treatment.. ST09 shows an approximate 100-fold higher potency than curcumin, its parent compound, on breast tumor cell lines MCF-7 and MDA-MB231. ST09 arrests the cell cycle in a cell type-specific manner and induces an intrinsic apoptotic pathway both in vitro and in vivo. ST09 inhibits migration by downregulating matrix metalloprotease 1,2 (MMP1,2) and Vimentin. In vivo, ST09 administration led to decreased tumor volume in a mouse allograft model by boosting immunity with no significant drug toxicity.. ST09 exhibits antiproliferative and cytotoxic activity at nanomolar concentrations. It induces cell death by activation of the intrinsic pathway of apoptosis both in vitro and in vivo. It also inhibits migration and invasion. This study provides evidence that ST09 can potentially be developed as a novel antitumor drug candidate for highly metastatic and aggressive breast cancer.

Topics: Allografts; Animals; Breast Neoplasms; Cell Cycle Checkpoints; Cell Death; Cell Line, Tumor; Cell Movement; Curcumin; Disease Models, Animal; Disease Progression; Female; Humans; Inhibitory Concentration 50; Mammary Neoplasms, Animal; Matrix Metalloproteinases; Membrane Potential, Mitochondrial; Mice; Toxicity Tests

Combination therapy by two or multiple drugs with different mechanisms of action is a promising strategy in cancer treatment. In this regard, a wide range of chemotherapeutics has used simultaneously to achieve the synergistic effect and overcome the adverse side effects of single-drug therapy. Herein, we developed a biocompatible nanoparticle-based system composed of nanocrystalline cellulose (NCC) and amino acid l-lysine for efficient co-delivery of model chemotherapeutic methotrexate (MTX) and polyphenol compound curcumin (CUR) to the MCF-7 and MDA-MB-231 cells. The drugs could release in a sustained and acidic-facilitate manner. In vitro cytotoxicity results represented the superior anti-tumor efficacy of the dual-drug-loaded nanocarriers. Possible inhibition of cell growth and induction of apoptosis in the cells treated with different formulations of CUR and MTX were explored by cell cycle analysis and DAPI staining. Overall, the engineered nanosystem can be used as suitable candidates to achieve efficient multi-drug delivery for combination cancer therapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Breast Neoplasms; Cell Cycle; Cell Proliferation; Cellulose; Curcumin; Drug Carriers; Drug Delivery Systems; Drug Liberation; Female; Humans; Lysine; Methotrexate; Nanoparticles; Tumor Cells, Cultured

The spread of a primary malignant tumor is the major reason for most of the cancer-associated deaths. To this day, treatment regimen and available drugs are still insufficient to manage these conditions. In this work, a new therapeutic concept based on photodynamic therapy (PDT) of metastasis-initiating cells is introduced. To address this issue, an experimental model was developed to simulate the movement and photodynamic inactivation of circulating tumor cells (CTCs) in vitro. Using curcumin loaded poly(lactic-co-glycolic acid) nanoparticles, a significant reduction in the cell viability of human breast cancer cells (MDA-MB-231) could be achieved after 30 min laser irradiation (λ = 447 nm, P = 100mW) under flow conditions (5 cm s

Topics: Apoptosis; Breast Neoplasms; Cell Line, Tumor; Curcumin; Drug Carriers; Drug Compounding; Female; Humans; Microscopy, Confocal; Microscopy, Electrochemical, Scanning; Nanoparticles; Necrosis; Neoplasm Metastasis; Neoplastic Cells, Circulating; Photochemotherapy; Photosensitizing Agents; Polylactic Acid-Polyglycolic Acid Copolymer

Active growth hormone (GH) signaling triggers cellular growth and invasion-metastasis in colon, breast, and prostate cancer. Curcumin, an inhibitor of NF-ҡB pathway, is assumed to be a promising anti-carcinogenic agent. Atiprimod is also an anti-inflammatory, anti-carcinogenic agent that induces apoptotic cell death in hepatocellular carcinoma, multiple myeloma, and pituitary adenoma. We aimed to demonstrate the potential additional effect of atiprimod on curcumin-induced apoptotic cell death via cytokine expression profiles in MCF-7 and MDA-MB-231 cells with active GH signaling. The effect of curcumin and/or atiprimod on IL-2, IL-4, and IL-17A levels were measured by ELISA assay. MTT cell viability, trypan blue exclusion, and colony formation assays were performed to determine the effect of combined drug exposure on cell viability, growth, and colony formation, respectively. Alteration of the NF-ҡB signaling pathway protein expression profile was determined following curcumin and/or atiprimod exposure by RT-PCR and immunoblotting. Finally, the effect of curcumin with/without atiprimod treatment on Reactive Oxygen Species (ROS) generation and apoptotic cell death was examined by DCFH-DA and Annexin V/PI FACS flow analysis, respectively. Autocrine GH-mediated IL-6, IL-8, IL-10 expressions were downregulated by curcumin treatment. Atiprimod co-treatment increased the inhibitory effect of curcumin on cell viability, proliferation and also increased the curcumin-triggered ROS generation in each GH

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Proliferation; Cell Survival; Curcumin; Cytokines; Female; Human Growth Hormone; Humans; MCF-7 Cells; Spiro Compounds

Topics: Administration, Oral; Animals; Antineoplastic Combined Chemotherapy Protocols; Biological Availability; Breast Neoplasms; Caco-2 Cells; Cardiotoxicity; Curcumin; Disease Models, Animal; Doxorubicin; Drug Carriers; Drug Stability; Drug Synergism; Female; Humans; Intestinal Absorption; Male; Mice; Nanoparticles; Particle Size; Polyesters; Polyethylene Glycols; Rats; Tissue Distribution

Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Curcumin; Drug Carriers; Drug Delivery Systems; Female; Humans; Lipoproteins; Mice; Nanoparticles; Particle Size; Serum Albumin, Human

Ferroptosis is a form of oxidative cell death and has become a chemotherapeutic target for cancer treatment. Curcumin (CUR), a well-known cancer inhibitor, significantly inhibits the viability of breast cancer cells. Through transcriptomic analysis and flow cytometry experiments, it was found that after 48 hours of treatment of breast cancer cells at its half maximal inhibitory concentration (IC50), curcumin suppressed the viability of cancer cells via induction of ferroptotic death. Use of the ferroptosis inhibitor ferrostatin-1 and the iron chelator deferoxamine rescued cell death induced by curcumin. Furthermore, in subsequent cell validation experiments, the results showed that curcumin caused marked accumulation of intracellular iron, reactive oxygen species, lipid peroxides, and malondialdehyde, while glutathione levels were significantly downregulated. These changes are all manifestations of ferroptosis. Curcumin upregulates a variety of ferroptosis target genes related to redox regulation, especially heme oxygenase-1 (HO-1). Using the specific inhibitor zinc protoporphyrin 9 (ZnPP) to confirm the above experimental results showed that compared to the curcumin treatment group, treatment with ZnPP not only significantly improved cell viability but also reduced the accumulation of intracellular iron ions and other ferroptosis-related phenomena. Therefore, these data demonstrate that curcumin triggers the molecular and cytological characteristics of ferroptosis in breast cancer cells, and HO-1 promotes curcumin-induced ferroptosis.

Topics: Breast Neoplasms; Curcumin; Female; Ferroptosis; Heme Oxygenase-1; Humans; Iron; Lipid Peroxidation; Protoporphyrins; Reactive Oxygen Species; Transcriptome

Orthogonal experiments were used to optimize the process parameters of curcumin TPP-PEG-PCL nanomicelles; the particle size, electric potential and morphology under the electron microscope were systematically detected for the curcumin TPP-PEG-PCL nanomicelles; and the stability and in vitro release of the curcumin TPP-PEG-PCL nanomicelles were investigated. With DID fluorescent dye as the fluorescent probe, flow cytometry was used to study the uptake of nanomicelles by breast cancer cells, and laser confocal microscopy was used to study the mitochondrial targeting and lysosomal escape functions of nanomicelles. Under the same dosage conditions, the effect of curcumin TPP-PEG-PCL nanomicelles on promoting the apoptosis of breast cancer cells was evaluated. The optimal particle size of curcumin TPP-PEG-PCL nanomicelle was(17.3±0.3) nm, and the Zeta potential was(14.6±2.6) mV in orthogonal test. Under such conditions, the micelle appeared as regular spheres under the transmission electron microscope. Fluorescence test results showed that TPP-PEG-PCL nanomicelles can promote drug uptake by tumor cells, escape from lysosomal phagocytosis, and target the mitochondria. The cell survival rate and Hoechst staining positive test results showed that curcumin TPP-PEG-PCL nanomicelles had a good effect on promoting apoptosis of breast cancer cells. The curcumin TPP-PEG-PCL micelles can significantly reduce the mitochondrial membrane potential of breast cancer cells, increase the release of cytochrome C, significantly increase the expression of pro-apoptotic protein Bcl-2 and reduce the expression of anti-apoptotic Bax protein. These test results were significantly better than those of curcumin PEG-PCL nanomicelles and curcumin, with statistically significant differences. The results revealed that curcumin TPP-PEG-PCL nanomicelles can well target breast cancer cell mitochondria and escape from the lysosomal capture, thereby enhancing the drug's role in promoting tumor cell apoptosis.

Topics: Apoptosis; Breast Neoplasms; Cell Line, Tumor; Curcumin; Humans; Lysosomes; Micelles; Mitochondria; Phosphatidylethanolamines; Polyethylene Glycols

Breast cancer stem cells are an important cause of radiotherapy resistance in the clinical treatment of breast cancer patients. How to target breast cancer stem cells is the key to improving the efficacy of breast cancer radiotherapy. We proposed for the first time that curcumin combined with glucose nanogold particles (Glu-GNPs) targeted breast cancer stem cells to reduce radiotherapy resistance, which can significantly enhance the apoptosis level of MCF-7 and MDA-MB-231 breast cancer stem-like cells (BCSCs) after radiotherapy and antiproliferation and colony-forming. Under simulated hypoxic conditions, curcumin combined with Glu-GNPs can significantly improve the ROS level of MCF-7 and MDA-MB-231 mammospheres; reduce the expression of HIF-1

Topics: Apoptosis; Breast Neoplasms; CD24 Antigen; Cell Adhesion; Cell Cycle; Cell Line, Tumor; Cell Survival; Curcumin; Female; Gene Expression Profiling; Glucose; Humans; Hyaluronan Receptors; Hypoxia; MCF-7 Cells; Metal Nanoparticles; Nanomedicine; Nanoparticles; Neoplastic Stem Cells; Radiation Tolerance; Radiation-Sensitizing Agents; Radiotherapy; Reactive Oxygen Species

Vast therapeutic traits and very low toxicity of curcumin compound have made it and related formulations promising for treatment purposes. The aim of this study was the assessment of dendrosome curcumin (DNC) inhibitory effects on breast cancer therapy compared to single curcumin compound.. DNC was synthesized and MCF-7 cells were prepared. The cultured cells were treated with 20 μg/ml and 25 μg/ml of DNC. Real-time quantitative PCR (RT-qPCR) was performed to measure the expression of FOXCUT and MEG3 genes. Additionally, flow cytometry was applied to measure cell death rate and apoptosis.. The results outlined that DNC enhanced the MEG3 gene expression significantly higher than the control. Furthermore, DNC was associated with a significant decrease in the expression of FOXCUT gene as compared to the control. The application of DNC in the MCF7 cell line enhanced cell death and reduced necrosis.. The rate of apoptosis (programmed cell death) was enhanced, but necrosis was decreased in treated cancer cells compared to those treated with single curcumin. Accordingly, the DNC can be applied to hinder the growth and dissemination of cancer cells as a preferred approach to reduce the complications of other strategies such as chemotherapy and radiation therapy. Indeed, we concluded that DNC enhanced the expression of MEG3, a tumor suppressor, at 25 μm dose, but reduced the expression of the FOXCUT gene, possibly via the methylation of the gene. Thereby, DNC exerted a promising tumor inhibitory growth potential for the eradication of cancer cells.

Topics: Apoptosis; Breast Neoplasms; Curcumin; Drug Carriers; Female; Gene Expression; Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); Humans; MCF-7 Cells; RNA, Long Noncoding

and purpose: Phytochemicals are proven to be effective in targeting numerous signaling pathways in cancer. Utilizing plant-based support in combination with currently approved chemotherapeutic strategies might prove a feasible method to improve therapeutic outcomes in cancer patients. The present study aimed to estimate the effect of turmeric supplementation on quality of life (QoL) and hematological parameters in breast cancer patients on Paclitaxel chemotherapy.. The present study is a prospective consecutive case series with 60 participants. QoL was assessed using a standard questionnaire and hematological parameters were recorded from the patients' hospital records.. Turmeric supplementation for 21 days resulted in clinically relevant and statistically significant improvement in global health status, symptom scores (fatigue, nausea, vomiting, pain, appetite loss, insomnia), and hematological parameters.. The study findings show that turmeric supplementation improved QoL, brought about symptom palliation and increased hematological parameters in breast cancer patients.

Topics: Breast Neoplasms; Curcuma; Dietary Supplements; Humans; Paclitaxel; Prospective Studies; Quality of Life

Over the past few years, fabrication of nanoparticles (NPs) has been deployed widely in technologies and many concerns have emerged about the hazardous effect on human health after NPs exposure.. Green synthesis of gold NPs (AuNPs) and assessment of their activity in 7,12-dimethylbenz(a)anthracene (DMBA)-induced breast cancer mouse model.. Chloroauric acid (HAuCl4) was used in formation of AuNPs with the help of Curcuma longa as aqueous reducing extract and stabilizing agent at room temperature. Formed NPs were characterized with UV-Vis spectrometry, Fourier-transform infrared spectroscopy (FTIR), Zetasizer measurement, Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM). Virgin female albino mice with DMBA-induced breast cancer were treated with formed AuNPs for 5 consecutive days and were dissected after 28 days of the beginning of treatment.. UV-Vis spectrometry showed absorbance maximum peak at 530 nm for formed AuNPs, FTIR confirmed formation of plant extract layer around formed NPs; zetasizer measurement revealed 278.2 nm as an average size of produced NPs; SEM and TEM approved formation of monodisperse spherical AuNPs. Biochemical analysis of untreated breast cancer group revealed marked changes in liver and kidney functions manifested by raised activity levels of alanine transaminase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN) and creatinine. Whereas, the treated group with AuNPs post-breast cancer induction displayed reduction in the activities (of ALT, AST and creatinine), while the BUN activity level was raised. Histopathological examination showed heavy incidence of tumor foci in the breast and lymph nodes belonged to the untreated breast cancer group confirmed with intense response to Ki-67 antibodies. While the treated group with AuNPs post-breast cancer induction showed degenerated tumor foci in the breast and lymph nodes with weak response to Ki-67 antibodies.. AuNPs were successfully synthesized using HAuCl4 and C. longa extract confirmed their ability to control DMBA-induced breast cancer in virgin female Swiss albino mice.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Alanine Transaminase; Animals; Antineoplastic Agents; Aspartate Aminotransferases; Blood Urea Nitrogen; Breast Neoplasms; Cell Proliferation; Chlorides; Creatinine; Curcuma; Excipients; Female; Gold Compounds; Green Chemistry Technology; Metal Nanoparticles; Mice; Nanomedicine; Neoplasms, Experimental; Oxidation-Reduction; Plant Extracts; Tumor Burden

Homogeneous PEGylated lipid bilayer coated highly ordered MSNs (PLMSNs) which were systematically optimized and characterized to co-encapsulate paclitaxel (Tax) and curcumin (Cur) were verified to manifest prolonged and enhanced cytotoxic effect against canine breast cancer cells in our previous study. In this article, we took further study of the pharmacokinetic property, cellular uptake, subcellular localization, in vivo distribution and tumor accumulation ability, and treatment efficacy of the drug delivery system. The results revealed that the delivery system could significantly increase the AUC of two drugs, and the anti-tumor effect showed that both intravenous and intratumoral administration group better controlled the tumor weight than that of other groups (P < .05), and the anti-tumor rates were 58.4% and 58.3% respectively. Cell uptake and localization study showed that PLMSNs could effectively carry drugs into cancer cells with sustained release characteristics. The subcellular localization of PLMSNs was mainly in lysosomes and mitochondria. In vivo fluorescence tracing results showed that PLMSNs could be effectively accumulated in the tumor site. The results revealed that the delivery system could effectively reduce the clinical dosage of drugs and reduce its toxic side effects, effectively carry drugs into cancer cells, and exhibit good targeting characteristics for breast cancer.

Topics: Animals; Antineoplastic Agents; Biological Transport; Breast Neoplasms; Cell Line, Tumor; Cell Survival; Curcumin; Dogs; Drug Compounding; Drug Liberation; Drug Therapy, Combination; Female; Humans; Lipid Bilayers; Lysosomes; Mice, Inbred BALB C; Mice, Nude; Mitochondria; Nanocapsules; Paclitaxel; Polyethylene Glycols; Porosity; Rats, Sprague-Dawley; Silicon Dioxide; Surface Properties; Tumor Burden

In this study, novel multifunctional folic acid, biotin, and CD44 receptors targeted and pH-sensitive "nano-actiniaes" were fabricated with icariin (ICA) and curcumin (Cur) as loaded model drugs for breast cancer therapy. The newly synthesized polymer oligomeric hyaluronic acid-hydrazone bond-folic acid-biotin (Bio-oHA-Hyd-FA) was characterized by

Topics: Animals; Antineoplastic Agents; Biotin; Breast Neoplasms; Curcumin; Drug Carriers; Drug Delivery Systems; Female; Folic Acid; Humans; Hyaluronan Receptors; Hyaluronic Acid; Hydrogen-Ion Concentration; MCF-7 Cells; Mice, Nude; Micelles; Particle Size; Polymers; Sea Anemones

Nanoparticulate delivery systems have been noticed for chemotherapeutical delivery due to their ability in controlling the drug release and reducing the side effect. These systems could also be used to deliver two drugs or more simultaneously, inhibiting the development of resistant cancerous cells. Methotrexate (MTX), one of the most frequently used chemotherapeutic agent, and Curcumin (CUR), a natural chemopreventive compound, have shown promising results in treatment or controlling the progression of cancer. The aim of this study is to prepare and evaluate polymeric nanoparticles for co-delivery of MTX and CUR. The PLGA nanoparticles were prepared and characterized in respect of their particles size, morphology, drug encapsulation efficiencies, release patterns, cell cytotoxicity, and in vivo efficacy. Altering MTX and CUR amounts leads to particle size of 142.3 ± 4.07 nm with MTX encapsulation efficiency of 71.32 ± 7.8% and CUR encapsulation efficiency of 85.64 ± 6.3%. These particles showed significantly higher cytotoxicity in comparison with free MTX or CUR or even their solo-loaded formulations. The in vivo results showed the synergic effect of MTX and CUR co-delivery on inhibiting the progression of breast cancer. Considering the appropriate in vitro properties of acquired nanoparticles for controlled drug delivery and the satisfactory in vivo efficacy results, it seems that the prepared formulation is a promising candidate for further in vivo studies.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; Dose-Response Relationship, Drug; Drug Carriers; Drug Delivery Systems; Drug Liberation; Drug Screening Assays, Antitumor; Female; Humans; Methotrexate; Nanoparticles; Particle Size; Polylactic Acid-Polyglycolic Acid Copolymer; Structure-Activity Relationship; Surface Properties

Curcumin is known for its multitude of medicinal properties, including anti-cancer and migrastatic activity. Efforts to overcome poor bioavailability, stability, and side effects associated with the higher dose of curcumin has led to the development of newer derivatives of curcumin. Thus, the focus of this study is to screen novel curcumin derivatives, namely ST03 and ST08, which have not been reported before, for their cytotoxicity and migrastatic property on cancer cells.. Anti-cancer activity of ST03 and ST08 was carried out using standard cytotoxicity assays viz., LDH, MTT, and Trypan blue on both solid and liquid cancer types. Flow cytometric assays and western blotting was used to investigate the cell death mechanisms. Transwell migration assay was carried out to check for migrastatic properties of the compounds.. Both the compounds, ST03 and ST08, showed ~ 100 fold higher potency on liquid and solid tumour cell lines compared to its parent compound curcumin. They induced cytotoxicity by activating the intrinsic pathway of apoptosis in the breast (MDA-MB-231) and ovarian cancer cell lines (PA-1) bearing metastatic and stem cell properties, respectively. Moreover, ST08 also showed inhibition on breast cancer cell migration by inhibiting MMP1 (matrix metalloproteinase 1).. Both ST03 and ST08 exhibit anti-cancer activity at nanomolar concentration. They induce cell death by activating the intrinsic pathway of apoptosis. Also, they inhibit migration of the cancer cells by inhibiting MMP1 in breast cancer cells.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Curcumin; Drug Screening Assays, Antitumor; Female; Humans; Matrix Metalloproteinase 1; Molecular Structure; Ovarian Neoplasms

Breast cancer is the most prevalent cancer among women worldwide. WZ35, an analog of curcumin, has been demonstrated to remarkably improve the pharmacokinetic profiles in vivo compared with curcumin. WZ35 exhibits promising antitumor activity in gastric cancer, HCC, colon cancer. However, antitumor effects of WZ35 in breast cancer and its underlying molecular mechanisms remain unclear.. CCK8, Flow cytometry and transwell assays were used to measure cell proliferation, cell cycle arrest, apoptosis, cell migration and invasion. We constructed xenograft mouse model and lung metastasis model to assess the antitumor activities of WZ35 in vivo. To explore the underlying molecular mechanisms of WZ35, we performed a series of overexpression and knockdown experiments. The cellular oxygen consumption rates (OCRs) was measured to assess mitochondrial dysfunction.. We found that treatment of breast cancer cells with WZ35 exerts stronger anti-tumor activities than curcumin both in vitro and in vivo. Mechanistically, our research showed that WZ35 induced reactive oxygen species (ROS) generation and subsequent YAP mediated JNK activation in breast cancer cells. Abrogation of ROS production markedly attenuated WZ35 induced anti-tumor activities as well as YAP and JNK activation. In addition, ROS mediated YAP and JNK activation induced mitochondrial dysfunction in breast cancer cells.. Our study showed that novel anti-cancer mechanisms of WZ35 in breast cancer cells and ROS-YAP-JNK pathway might be a potential therapeutic target for the treatment of breast cancer patients.

Topics: Adaptor Proteins, Signal Transducing; Animals; Apoptosis; Breast Neoplasms; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; Disease Models, Animal; Female; Humans; JNK Mitogen-Activated Protein Kinases; Mice; Mitochondria; Models, Biological; Oxidative Phosphorylation; Prognosis; Reactive Oxygen Species; Transcription Factors; Xenograft Model Antitumor Assays; YAP-Signaling Proteins

Curcumin has been widely used owing to its various medicinal properties including antitumor effects. However, its clinical application is limited by its instability, poor solubility and low bioavailability. Folic acid (FA)-functionalized nanoformulations may enhance the sustained release of an anticancer drug (curcumin) by tumor-specific targeting to improve therapeutic benefit. This study aims to design a nanoconjugate (NC) comprised of folate-curcumin-loaded gold-polyvinylpyrrolidone nanoparticles (FA-CurAu-PVP NPs) for targeted delivery in breast cancer model systems.. We developed curcumin-loaded FA-functionalized Au-PVP NCs by layer-by-layer assembly. The folic acid-curcumin Au-PVP NCs (FA-CurAu-PVP NCs) were characterized by ultraviolet-visible spectra, Fourier transform infrared spectroscopy, X-ray powder diffraction and thermogravimetric analysis. In vitro anticancer and antimigratory effects of NCs were examined by performing MTT and wound migration assays. The in vivo antitumor efficacy of NCs was investigated using a preclinical breast cancer orthotopic mouse model.. Curcumin (40 µg/mL) was loaded along with conjugation of folate onto Au-PVP NPs to form FA-CurAu-PVP NCs. The size and charge of the NCs were increased gradually through layer-by-layer assembly and showed 80% release of curcumin at acidic pH. The NC did not show aggregation when incubated with human serum and mimicked an intrinsic peroxidase-like property in the presence of 3,3',5,5'-tetramethylbenzidine substrate. The MTT data using these NCs showed efficient anticancer activity at lower doses in estrogen/progesterone receptor (ER/PR)-negative cells compared with ER/PR-positive cells. Furthermore, the NCs did not show cytotoxicity at the investigated concentration in human breast epithelial and mouse fibroblast cell lines. They showed inhibitory effects on cell migration and high antitumor efficacy in in vivo analysis.. These results suggest that folate-based tumor targeting using CurAu-PVP NCs is a promising approach for tumor-specific therapy of breast cancer without harming normal cells.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Curcumin; Drug Carriers; Drug Delivery Systems; Drug Liberation; Female; Folic Acid; Gold; Humans; Hydrogen-Ion Concentration; Metal Nanoparticles; Mice; Nanoconjugates; Polymers; Povidone; Serum

N.B. This manuscript is based on the research concept submitted to the "Global Challenge to Prevent Breast Cancer" idea showcase and competition, launched in 2018 by the California Breast Cancer Research Program (CBCRP), which was subsequently selected for publication. The hypothesis, methods, and discussion put forth here are thus proposed concept studies, which could eventually be elucidated in the future. Curcumin is an herbal supplement, shown in preclinical studies to have antioxidant, anti-inflammatory, and antitumoral properties that we believe can be harnessed for breast cancer prevention. However, due to its poor absorption when consumed orally, curcumin's anticancer effects have not yet been exploited to their full therapeutic potential. Incorporating existing research that focuses on the optimization of curcumin's bioavailability and the latest transdermal delivery technology, we propose, below, a hypothetical in vivo study to test whether a targeted daily dose of bioavailable curcumin has a cytotoxic effect on cancer cells, potentially reducing the incidence of breast cancer over time. Our ultimate objective is to adopt innovative methods to create curcumin-infused bio-textiles offering transdermal, targeted drug delivery, simply through contact with the skin. We would use this fabric to create disposable bra inserts for an effortless, daily breast cancer prevention regimen for healthy women. It would be essential that the cost of these inserts remain reasonable, but if successful, curcumin is readily available, affordable and non-toxic, and could thus be a preventive measure that would be beneficial for women from all socio-economic backgrounds.

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Biological Availability; Breast Neoplasms; Curcumin; Female; Heterografts; Humans; Mice; Skin Absorption

Curcumin is a natural derivative, which exhibits broad spectrum biological activities including anti-oxidant, anti-inflammatory, and anti-cancer. Since ancient times, it has been used for the treatment of various diseases. Many reports highlighted its potential as a chemopreventive and chemotherapeutic agent. Despite its imperative properties, the pharmacological application had been limited due to low solubility in the aqueous medium, limited tissue absorption, and rapid degradation at physiological pH.. Cytotoxicity of drugs and their undesirable side effects are major obstacles in the regimens of cancer therapy. Therefore, natural plant derivatives-based anti-cancer drug delivery systems are getting more attention as they are less toxic, safer, and effective. In the present study, Pluronic block copolymer encapsulated curcumin was developed as an improved curcumin delivery system with the aim to improve its efficacy and biological response against cancer cells.. Pluronic micelles encapsulated curcumin was synthesized, and its characterization was done by particle size analysis, Fourier transform infrared spectroscopy, small-angle neutron scattering analysis, PXRD, and differential scanning calorimetry. Further, its biological activities were corroborated in cancer cells. Results indicate that Pluronic micelles encapsulated curcumin exemplify solubility and stability of curcumin in the aqueous medium. Biophysical characterization indicated that Pluronic F127 forms nanoparticle, and its micellar core radius was increased after incorporation of curcumin. Furthermore, biological studies show that Pluronic micelles encapsulated curcumin inhibits cell proliferation, improves cellular uptake of curcumin, arrests the cell cycle in G0/G1 phase, and inhibits the activation of NF-kB and release of pro-inflammatory cytokines to manifest apoptotic cell death rather than necrotic. This formulation was non-toxic to normal cells.. This study suggests that Pluronic micelles encapsulated curcumin is stable that can effectively inhibit cell proliferation and release of pro-inflammatory cytokines in cancer cells as compared with the free curcumin. This approach could be applied to improve the therapeutic index of anti-cancer agents.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Breast Neoplasms; Cell Line; Cell Line, Tumor; Curcumin; Cytokines; Drug Carriers; Female; Humans; Mice; Micelles; Poloxamer

Curcumin and salicylic acid are both phenolic compounds and they can both affect cancer treatment efficacy. In this study, the effects of methylene blue-curcumin (CU-MB) and methylene blue-salicylic acid (SA-MB) ion pair complexes on MDA-MB-231 human breast cancer cells are studied. According to the thermodynamic parameters, the stability of curcumin and salicylic acid complexes ion pair complexes was compared. The free energy of ion pair interactions was calculated based on binding constants. A comparison of the free energies of the complexes (CU-MB: ∆G

Topics: Apoptosis; Breast Neoplasms; Cell Death; Cell Line, Tumor; Cell Shape; Cell Survival; Curcumin; Female; Humans; Ions; Light; Methylene Blue; Phenols; Photochemotherapy; Photosensitizing Agents; Salicylic Acid; Spectrum Analysis; Thermodynamics

Breast cancer (BCa) bone metastases (BMETs) drive osteolysis via a feed-forward loop involving tumoral secretion of osteolytic factors (e.g., PTHrP) induced by bone-matrix-derived growth factors (e.g., TGFβ). In prior experiments, turmeric-derived curcumin inhibited in vivo BMET progression and in vitro TGFβ/Smad-signaling in a TGFβ-stimulated PTHrP-dependent human xenograft BCa BMET model (MDA-SA cells). However, it is unclear whether curcumin or curcumin-glucuronide mediates in vivo protection since curcumin-glucuronide is the primary circulating metabolite in rodents and in humans. Thus, effects of curcumin vs. curcumin-glucuronide on Smad-dependent TGFβ signaling were compared in a series of BCa cell lines forming TGFβ-dependent BMET in murine models, and tissue-specific metabolism of curcumin in mice was examined by LC-MS. While curcumin inhibited TGFβ-receptor-mediated Smad2/3 phosphorylation in all BCa cells studied (human MDA-SA, MDA-1833, MDA-2287 and murine 4T1 cells), curcumin-glucuronide did not. Similarly, curcumin, but not curcumin-glucuronide, blocked TGFβ-stimulated secretion of PTHrP from MDA-SA and 4T1 cells. Because the predominant serum metabolite, curcumin-glucuronide, lacked bioactivity, we examined tissue-specific metabolism of curcumin in mice. Compared to serum and other organs, free curcumin (both absolute and percentage of total) was significantly increased in bone, which was also a rich source of enzymatic deglucuronidation activity. Thus, curcumin, and not curcumin-glucuronide, appears to inhibit bone-tropic BCa cell TGFβ-signaling and to undergo site-specific activation (deconjugation) within the bone microenvironment. These findings suggest that circulating curcumin-glucuronide may act as a prodrug that preferentially targets bone, a process that may contribute to the bone-protective effects of curcumin and other highly glucuronidated dietary polyphenols.

Topics: Administration, Oral; Animals; Antineoplastic Agents, Phytogenic; Bone Neoplasms; Breast Neoplasms; Cell Line, Tumor; Curcumin; Female; Glucuronides; Humans; Mice; Mice, Inbred C57BL; Parathyroid Hormone-Related Protein; Signal Transduction; Smad Proteins; Transforming Growth Factor beta

Autocrine growth hormone (GH) signaling is a promoting factor for breast cancer via triggering abnormal cell growth, proliferation, and metastasis, drug resistance. Curcumin (diferuloylmethane), a polyphenol derived from turmeric (Curcuma longa), has anti-proliferative, anti-carcinogenic, anti-hormonal effect via acting on PI3K/Akt, NF-κB and JAK/STAT signaling. Forced GH expression induced epithelial mesenchymal transition (EMT) through stimulation of miR-182-96-183 cluster expression in breast cancer cells. This study aimed to investigate the role of NF-κB signaling and miR-182-96-183 cluster expression profile on autocrine GH-mediated curcumin resistance, which was prevented by time-dependent curcumin treatment in T47D breast cancer cells. Dose- and time-dependent effect of curcumin on T47D wt and GH+ breast cancer cells were evaluated by MTT cell viability and trypan blue assay. Apoptotic effect of curcumin was determined by PI and Annexin V/PI FACS flow analysis. Immunoblotting performed to investigate the effect of curcumin on PI3K/Akt/MAPK, NF-κB signaling. miR182-96-183 cluster expression profile was observed by qRT-PCR. Overexpression of GH triggered resistant profile against curcumin (20 µM) treatment for 24 h, but this resistance was accomplished following 48 h curcumin exposure. Concomitantly, forced GH induced invasion and metastasis through EMT and NF-κB activation were prevented by long-term curcumin exposure in T47D cells. Moreover, 48 h curcumin treatment prevented the autocrine GH-mediated miR-182-96-183 cluster expression stimulation in T47D cells. In consequence, curcumin treatment for 48 h, prevented autocrine GH-triggered invasion-metastasis, EMT activation through inhibiting NF-κB signaling and miR-182-96-183 cluster expression and induced apoptotic cell death by modulating Bcl-2 family members in T47D breast cancer cells.

Topics: Apoptosis; Autocrine Communication; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Curcuma; Curcumin; Epithelial-Mesenchymal Transition; Female; Human Growth Hormone; Humans; MicroRNAs; Mitogen-Activated Protein Kinases; NF-kappa B; Phosphatidylinositol 3-Kinases; Plant Extracts; Proto-Oncogene Proteins c-akt; Signal Transduction

Protein tyrosine phosphatase (PTP1B) is a potential target for the treatment of type 2 diabetes and cancer. Curcumin and cinnamaldehyde have been previously reported to have antidiabetic and anticancer potentials. The aim of this study was to investigate the effect of curcumin in comparison to cinnamaldehyde on the enzymatic activity of PTP1B and the viability of MCF-7 cancer cells.. Enzymatic activity and cell viability assays were utilized. Experiments were performed using the breast cancer MCF-7 cell line.. Curcumin and cinnamaldehyde decreased the activity of PTP1B, and had inhibitory effects on the viability of MCF-7 cancer cells. Curcumin had a significantly higher inhibitory effect than cinnamaldehyde.. Curcumin can be considered a potential agent for the treatment of type-2 diabetes or cancer.

Topics: Acrolein; Antineoplastic Agents; Breast Neoplasms; Cell Survival; Curcumin; Diabetes Mellitus, Type 2; Drug Screening Assays, Antitumor; Female; Humans; Hypoglycemic Agents; MCF-7 Cells; Protein Tyrosine Phosphatase, Non-Receptor Type 1

A cationic liposome-PEG-PEI complex (LPPC) was employed as a carrier for achieving targeted delivery of drug to human epidermal growth factor receptor-2 (HER2/neu)-expressing breast cancer cells. LPPC can be easily loaded with an anti-tumor drug and non-covalently associated with an anti-tumor antibody such as Herceptin that is clinically used to rapidly form immunoparticles within 1 h.. Drug-loaded LPPC have an average size about 250 nm and a zeta potential of about 40 mV. Herceptin was complexed onto surface of the LPPC to form the drug/LPPC/Herceptin complexes. The size of curcumin/LPPC/Herceptin complexes were 280 nm and the zeta potentials were about 23 mV. Targeting ability of this delivery system was demonstrated through specific binding on surface of cells and IVIS images in vivo, which showed specific binding in HER2-positive SKBR3 cells as compared to HER2-negative Hs578T cells. Only the drug/LPPC/Herceptin complexes displayed dramatically increased the cytotoxic activity in cancer cells. Both in vitro and in vivo results indicated that Herceptin adsorbed on LPPC directed the immunocomplex towards HER2/neu-positive cells but not HER2/neu-negative cells. The complexes with either component (curcumin or doxorubicin) used in the LPPC-delivery system provided a better therapeutic efficacy compared to the drug treatment alone and other treatment groups, including clinical dosages of Herceptin and LipoDox, in a xenografted model.. LPPC displays important clinical implications by easily introducing a specific targeting characteristic to drugs utilized for breast cancer therapy.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Proliferation; Cell Survival; Curcumin; Doxorubicin; Drug Liberation; Female; Heterografts; Humans; Liposomes; MCF-7 Cells; Mice, Inbred BALB C; Particle Size; Polyethylene Glycols; Polyethyleneimine; Receptor, ErbB-2; Surface Properties; Trastuzumab

Curcumin, the polyphenolic constituent of turmeric, has been recognized as an effective anticancer agent in the treatment of breast cancer. However, the poor bioavailability of curcumin triggers finding of new approaches for elevating its therapeutic efficiency.. We aimed to use gemini surfactant nanocarriers for curcumin in order to overcome its limitations.. We investigated the in vitro characterization of gemini surfactant-curcumin (Gemini-Cur) and examined its antiproliferative & apoptotic activities on breast cancer cell lines.. Gemini-Cur polymersomes were synthesized through nanoprecipitation method and characterized by dynamic light scattering (DLS), transmission and scanning electron microscopies, HPLC and X-ray diffraction (XRD). The anticancer effect of Gemini-Cur nanoparticles was studied on three different breast cancer cell lines including MCF-7, SkBr-3 and MDA-MB-231 through uptake kinetics, viability & cytotoxicity recordings and apoptotic assays. Furthermore, qRT-PCR was performed to evaluate the expression of apoptotic genes including p16INK4a, p14ARF, Bax and Bcl-2.. According to physicochemical analysis, the average particle size, zeta potential value and drug entrapment efficiency for Gemini-Cur compound were recorded as 161 ± 6.2 nm, +5.32 mV and 89.13% ± 0.93, respectively. XRD analysis also confirmed the incorporation of curcumin in gemini surfactant micelles. Regarding the enhanced cellular uptake of sphere shaped Gemini-Cur, our data showed that this nano compound suppresses cancer cell proliferation via induction of apoptosis. Moreover, qRT-PCR analysis revealed that Gemini-Cur could effectively upregulate the expression of p16INK4a, p14ARF and Bax, while significantly decreasing the Bcl-2 expression in these breast cancer cells.. Our data demonstrates the great potential of gemini surfactants for efficient delivery of curcumin and subsequently, the improvement of its anticancer effect. Therefore, it is sagacious to support the idea that Gemini-Cur nano compound might have the potential to be considered as an anticancer agent.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Curcumin; Drug Screening Assays, Antitumor; Dynamic Light Scattering; Female; Gene Expression Regulation, Neoplastic; Humans; Micelles; Nanoparticles; Particle Size; Surface-Active Agents; X-Ray Diffraction

In this study, an HER2 aptamer-decorated curcumin-loaded human serum albumin nanoparticle (Apt-HSA/CCM NP) was developed and characterized as a new anticancer formulation for targeted delivery to human epithelial growth factor receptor 2 (HER2) overexpressing breast cancer cells. Conjugation of HER2 Apt to the surface of HSA NPs was confirmed by gel electrophoresis and FTIR analysis. The obtained NPs have the hydrodynamic diameter of 281.1 ± 11.1 nm and zeta potential of -33.3 ± 2.5 mV. The data demonstrated that encapsulation of curcumin in HSA NPs by desolvation method has increased water solubility by 400 folds. Fluorescent microscopy image demonstrated remarkable cytoplasmic uptake of Apt-HSA/CCM NPs in HER2-overexpressing SK-BR-3 cells compared to unconjugated counterparts. Cytotoxicity experiments demonstrated no significant difference between cytotoxic effect of free curcumin and non-targeted HSA/CCM NPs in both HER2 positive and HER2 negative cell lines. However, the toxicity of Apt-HSA/CCM NPs was significantly higher and cell viability reached 36% after 72 h in SK-BR3 cell line. These results suggest that this targeted delivery system has the potential to be considered as a promising candidate for the treatment of HER2 positive cancer cells.

Topics: Aptamers, Nucleotide; Biological Transport; Breast Neoplasms; Cell Survival; Curcumin; Drug Carriers; Drug Liberation; Humans; MCF-7 Cells; Nanocomposites; Nanoparticles; Particle Size; Receptor, ErbB-2; Serum Albumin, Human

Curcumin is a natural polyphenolic compound with pronounced anticancer properties, despite its low bioavailability caused by extensive glucuronidation and sulfation. Information on the cellular uptake mechanisms and their contribution to the anticancer effects of curcumin and its biotransformation products is limited. The present study, therefore, investigated the role of organic anion‑transporting polypeptides (OATPs) in the cellular uptake of curcumin and its major metabolites in OATP‑expressing Chinese hamster ovary (CHO) and human ZR‑75‑1 breast cancer cells. The uptake rates for curcumin in OATP1B1‑, OATP1B3‑ and OATP2B1‑transfected CHO cells were 2‑ to 3‑fold higher than wild‑type cells. Curcumin sulfate was transported by all three OATPs, although to a much lesser extent, while uptake of tetrahydrocurcumin was the highest but only via OATP1B1 and OATP1B3. Notably, curcumin glucuronide did not exhibit any affinity for these OATPs. The increased mRNA levels of OATP1B1 in wild‑type human breast cancer ZR‑75‑1 cells compared with OATP1B1 knockdown cells was associated with a higher initial uptake of curcumin and tetrahydrocurcumin leading to decreased IC50 values. In conclusion, our data revealed that OATPs act as cellular uptake transporters for curcumin and its major metabolites, and this may also be applicable to patients undergoing cancer therapy.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Survival; CHO Cells; Cricetulus; Curcumin; Gene Knockdown Techniques; Humans; Organic Anion Transporters

Accumulating reports demonstrate that apoptosis does not explain all the effects of cancer therapy due to the innate and acquired apoptotic resistance of malignant cancer cells. Recently, paraptosis, a type of programmed cell death accompanied by dilation of mitochondria and/or the endoplasmic reticulum (ER), has garnered interest in cancer research as an alternative way to kill apoptosis-resistant cancers. We describe here the adaptation and validation of a high-content cell-based assay to screen and identify novel paraptotic regulators employing the malignant breast cancer cells undergoing curcumin-induced paraptosis. We used YFP-Mito cells, which express fluorescence selectively in mitochondria, to select paraptosis-related genes whose corresponding siRNAs appeared to modulate mitochondrial dilation, a morphological feature of paraptosis. From the selected 38 candidate genes, we chose ubiquitin specific peptidase 10 (USP10), a ubiquitin specific protease, as a strongly active candidate that warranted further evaluation of its involvement in paraptosis. We found that both siRNA-mediated knockdown of USP10 and treatment with the USP10 inhibitor, spautin-1, effectively attenuated curcumin-induced paraptosis. This systematic assay, in which a siRNA library is screened for the ability to ameliorate paraptotic changes in mitochondria, may enable researchers to identify potent regulators of paraptosis and new candidate genes/drugs to combat malignant breast cancer.

Topics: Antineoplastic Agents; Benzylamines; Breast Neoplasms; Cell Death; Cell Line, Tumor; Curcumin; Endoplasmic Reticulum; Female; Gene Library; High-Throughput Screening Assays; Humans; Membrane Potential, Mitochondrial; Mitochondria; Quinazolines; RNA Interference; RNA, Small Interfering; Ubiquitin Thiolesterase

Curcumin, a natural compound has several antineoplastic activities and is a promising natural photosensitizer used in photodynamic therapy. However, its low solubility in physiological medium limit the clinical use of curcumin. This study aimed to analyze the action of curcumin-nanoemulsion, a new and well-designed Drug Delivery System (DDS+) molecule, used as a photosensitizing agent in photodynamic therapy in an in vitro breast cancer model, MCF-7 cells. The empty nanoemulsion fulfils all necessary requirements to be an excellent DDS. Furthermore, the use of curcumin-nanoemulsion in photodynamic therapy resulted in a high phototoxic effect after activation at 440 nm, decreasing to <10% viable tumor cells after two irradiations and increasing the reactive oxygen species (ROS) production. The use of curcumin-nanoemulsion associated with photodynamic therapy resulted in an increase in the levels of caspase 3/7 activity for the studied MCF-7 cell model, indicating that this therapy triggers a cascade of events that lead to cell death, such as cellular apoptosis. In conclusion, curcumin-nanoemulsion proved to be efficient as a photosensitizing agent, had phototoxic effects, significantly decreased the proliferation of MCF-7 cells and stimulating the ROS production in combination with photodynamic therapy, so, this formulation has a great potential for use in treatment of breast cancer.

Topics: Apoptosis; Breast Neoplasms; Caspase 3; Caspase 7; Cell Proliferation; Curcumin; Female; Humans; Light; MCF-7 Cells; Nanostructures; Particle Size; Photochemotherapy; Photosensitizing Agents; Reactive Oxygen Species

In this study, we explored whether co-nanoencapsulated Curcumin (Cur) and Chrysin (Chr), natural herbal compounds with antitumor activities, regulate miR-132 and miR-502c and their downstream targets, leading to the synergistic growth inhibition in MDA-MB-231 breast cancer cells. For this purpose, Cur and Chr were co-encapsulated into PLGA-PEG nanoparticles (NPs) and characterized through DLS, FTIR and FE-SEM. MTT assay and cell cycle arrest analysis revealed that CurChr-loaded NPs had a considerable synergistic cytotoxicity against MDA-MB-231 cells with more cell accumulation in G2/M phase compared to the other groups. In addition, highest percentage of cell apoptosis was acquired in cells treated with CurChr-loaded NPs according to apoptosis analysis. Real-time PCR findings revealed that co-encapsulated form of Cur and Chr than free combination could further upregulate miR-132 and miR-502c expression (

Topics: Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Curcumin; Drug Delivery Systems; Drug Liberation; Flavonoids; Gene Expression Regulation, Neoplastic; Humans; MicroRNAs; Nanoparticles; Polyethylene Glycols; Polyglactin 910; Spectroscopy, Fourier Transform Infrared; Up-Regulation

Topics: Animals; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Curcumin; Drug Delivery Systems; Female; Humans; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Nanostructures; Neoplasms, Experimental; Topotecan; Ultrasonics

Doxorubicin is one of the most widely used chemotherapy agents for the treatment of breast cancer. However, the development of doxorubicin resistance limits the long‑term treatment benefits in patients with breast cancer. Curcumin, a well‑known dietary polyphenol derived from the rhizomes of turmeric (Curcuma longa), enhances the sensitivity of breast cancer cells to chemotherapeutic agents; however, the mechanisms underlying this phenomenon remain unclear. The aim of the present study was to evaluate the effect of curcumin on chemoresistance in doxorubicin‑resistant breast cancerMCF‑7/DOX and MDA‑MB‑231/DOX cell lines. Cell Counting Kit‑8, monolayer transport, western blot and ATPase activity assays were performed during the study. The results revealed that curcumin significantly enhanced the effect of doxorubicin in doxorubicin‑resistant breast cancer cells. The intracellular accumulation of doxorubicin was substantially increased following curcumin treatment in doxorubicin‑resistant breast cancer cells, in a manner that was inversely dependent on the activity of ATP binding cassette subfamily B member 4 (ABCB4). Treatment with a combination of curcumin and doxorubicin decreases the efflux of doxorubicin in ABCB4‑overexpressing cells. Furthermore, curcumin inhibited the ATPase activity of ABCB4 without altering its protein expression. In conclusion, curcumin reversed doxorubicin resistance in human breast cancer MCF‑7/DOX and MDA‑MB‑231/DOX cells by inhibiting the ATPase activity of ABCB4. The study highlights the promising use of curcumin as a chemosensitizer in the treatment of breast cancer.

Topics: Adenosine Triphosphatases; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Breast Neoplasms; Cell Survival; Curcumin; Dogs; Doxorubicin; Drug Resistance, Neoplasm; Female; Humans; Madin Darby Canine Kidney Cells; MCF-7 Cells

Photodynamic therapy (PDT) is a promising procedure for breast cancer therapy. Curcumin (Cur), a hydrophobic polyphenol derived from the spice turmeric, has been considered as a potential photosensitizer for PDT with evoked immune response, excellent safety, and low cost. However, the translation of curcumin in clinical cancer therapy suffers from an insufficient therapeutic dose in tumor tissues due to its poor solubility and low bioavailability. In this study, carrier-free curcumin nanodrugs (Cur NDs) were prepared without using any toxic solvents through a facile and green reprecipitation method. Cur NDs exhibited distinct optical properties, light-sensitive drug release behavior, resulting in increased reactive oxygen species (ROS) generation and PDT efficacy on breast cancer cells compared with free Cur. Furthermore, cell apoptosis during Cur-based PDT was concomitant with the activation of the ROS-mediated JNK/caspase-3 signaling pathway. Overall, our carrier-free Cur nanodrugs may be promising candidates for facilitating the efficacy and safety of PDT against breast cancer.

Topics: Animals; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Curcumin; Drug Carriers; Drug Liberation; Female; Green Chemistry Technology; Light; Mice; Nanoparticles; Photochemotherapy; Reactive Oxygen Species

Oral consumption of curcumin, a natural polyphenol, is associated with reduced incidence of cancer. Yet, a significant amount of the orally dosed compound is eliminated in the feces, and a major fraction of the absorbed compound is metabolized to inactive glucuronides, resulting in poor bioavailability (<1%). It is not known how oral curcumin exhibits chemopreventive activity. We propose curcumin glucuronide is an inflammation-responsive natural prodrug that is converted back to curcumin on demand at the site of action. Our studies show elevated levels of β-glucuronidase, an enzyme that hydrolyzes the glycosidic bond of glucuronides to generate the parent compound, in human breast cancer. Oral administration of curcumin in mouse tumor models generated significant tumor levels of the polyphenol. Intravenous administration of the glucuronide resulted in the formation of curcumin in the tumor tissue. Chronic daily oral curcumin dosing led to tumor accumulation of curcumin and inhibition of tumor growth in tumor models with high β-glucuronidase activity. Overall, the study presented here provides preliminary evidence for a novel mechanism of action for orally administered curcumin.-Liu, G., Khanna, V., Kirtane, A., Grill, A., Panyam, J. Chemopreventive efficacy of oral curcumin: a prodrug hypothesis.

Topics: Administration, Oral; Animals; Breast Neoplasms; Cell Line, Tumor; Curcumin; Drug Delivery Systems; Female; Glucuronidase; Glucuronides; Humans; Mice, Inbred BALB C; Mice, Nude; Prodrugs

Toll-like receptor 4 (TLR4) is over-expressed in breast tumors and thus contributing to the tumor progression and metastasis. Natural products have drawn attention in cancer immunotherapy due to their various biological activities. Curcumin is well investigated in different types of cancer. However, the mechanisms underlying its anti-inflammatory actions have not been extensively elucidated.  For this purpose, we explored the inhibitory effects of curcumin on lipopolysaccharide (LPS)-induced TLR4 dependent TRIF signaling pathway in two subtypes of breast cancer cell lines (MCF-7 and MDA-MB-231) in this study.. In this context, the cytotoxicity of curcumin and LPS alone and the combination of curcumin with LPS on these cells was evaluated by WST-1 assay.  The expression level of TLR4 and the release of type I interferon (IFN) levels were determined after treatment with curcumin and/or LPS by RT-PCR and ELISA analysis, respectively. Furthermore, the subcellular localization of TLR4 and interferon regulatory factor 3 (IRF3) were detected by immunofluorescence analysis.. Curcumin treatment suppressed breast cancer cells viabilities and the activation of TLR4-mediated TRIF signaling pathway by the downregulation of TLR4 and IRF3 expression levels and the inhibition of type I IFN (IFN-α/β) levels induced by LPS. However, curcumin was more efficient in MDA- MB-231 cells than MCF-7 cells owing to its greater inhibitory efficacy in the LPS- enhanced TLR4 signaling pathway. Furthermore, IFN-α/β levels induced by TLR4 and IRF3 were decreased in these cells following curcumin treatment.. Consequently, these results demonstrated that the activation of LPS stimulated TLR4/TRIF/IRF3 signaling pathway was mediated by curcumin in breast cancer cells, in vitro. However, more studies are necessary to examine the curcumin's anti-inflammatory activities on TLR4/MyD88/NF-κB as well as other signaling pathways downstream of TLRs in breast cancer.

Topics: Adaptor Proteins, Vesicular Transport; Anti-Inflammatory Agents; Breast Neoplasms; Cell Line, Tumor; Cell Survival; Curcumin; Humans; Interferon Regulatory Factor-3; Interferon-alpha; Interferon-beta; Lipopolysaccharides; Signal Transduction; Toll-Like Receptor 4

Non-spherical structures are beneficial to advance drug delivery effectiveness compared with common spherical ones, due to increased drug loading capability, improved bonding to a vascular wall, enhanced cellular uptake efficacy and prolonged circulation times. In this study, flower-like Zinc oxide-βcyclodextrin (βCD) nanostructures functionalized by 3-mercaptopropionic acid (MPA) as a non-spherical delivery system was successfully synthesized for aqueous delivery of curcumin (CUR) to enhance its targeting, bioavailability, and release profile. Terminal carboxyl functional groups were used for the conjugation of folic acid (FA) with the aim of active targeting to folate overexpressing breast cancer cells. The in vitro experimental study and mathematical modeling of CUR release revealed a sustained release with Fickian diffusion as the major release mechanism. MTT, colony formation and Annexin-V FITC/PI assays showed the superior anticancer effect of the system compared to free CUR against breast cancer cell line MDA-MB-231 by promoting the apoptotic respond with no cytotoxic effect on HEK293 normal cells. The efficacy of targeting strategy with FA moieties was demonstrated using the augmented cellular uptake of the FA-conjugated system on overexpressed folate receptor alpha (FRα) cells (MDA-MB-468 breast cancer cell line). Furthermore, loading of CUR to the delivery systems significantly lowered the MIC values (2.5 to 5-fold) against S. aureus and E. coli the infections of which are serious problems in cancer patients. According to the results of this study, the system can serve as a promising non-spherical delivery vehicle for enhancing bioavailability and targeting of hydrophobic anticancer agents in the future.

Topics: 3-Mercaptopropionic Acid; Antineoplastic Agents; Apoptosis; beta-Cyclodextrins; Breast Neoplasms; Cell Line, Tumor; Curcumin; Drug Carriers; Escherichia coli; Escherichia coli Infections; Female; Folic Acid; HEK293 Cells; Humans; Nanostructures; Staphylococcal Infections; Staphylococcus aureus; Zinc Oxide

In breast cancer (BC) care, radiotherapy is considered an efficient treatment, prescribed both for controlling localized tumors or as a therapeutic option in case of inoperable, incompletely resected or recurrent tumors. However, approximately 90% of BC-related deaths are due to the metastatic tumor progression. Then, it is strongly desirable to improve tumor radiosensitivity using molecules with synergistic action. The main aim of this study is to develop curcumin-loaded solid nanoparticles (Cur-SLN) in order to increase curcumin bioavailability and to evaluate their radiosensitizing ability in comparison to free curcumin (free-Cur), by using an in vitro approach on BC cell lines. In addition, transcriptomic and metabolomic profiles, induced by Cur-SLN treatments, highlighted networks involved in this radiosensitization ability. The non tumorigenic MCF10A and the tumorigenic MCF7 and MDA-MB-231 BC cell lines were used. Curcumin-loaded solid nanoparticles were prepared using ethanolic precipitation and the loading capacity was evaluated by UV spectrophotometer analysis. Cell survival after treatments was evaluated by clonogenic assay. Dose-response curves were generated testing three concentrations of free-Cur and Cur-SLN in combination with increasing doses of IR (2-9 Gy). IC

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Survival; Curcumin; Drug Carriers; Drug Delivery Systems; Female; Humans; Lipids; MCF-7 Cells; Nanoparticles; Particle Size; Radiation-Sensitizing Agents

To potentiate the anticancer activity of curcumin (CUR) by improving its cell penetration potentials through formulating it into nanostructured lipid carriers (NLCs) and using the prepared NLCs in photodynamic therapy.. A 3×4 factorial design was used to obtain 12 CUR-NLCs using two factors on different levels: (1) the solid lipid type at four levels and (2) the solid to liquid lipid ratio at three levels. Olive oil, Tween 80 and lecithin were chosen as liquid lipid, surfactant and co-surfactant, respectively. CUR-NLCs prepared by high shear hot homogenization method were evaluated by determination of particle size (PS), polydispersity index, zeta potential (ZP), entrapment efficiency percent, drug loading percent and in vitro drug release. Optimization was based on the evaluation results using response surface modeling (RSM). Optimized formulae were tested for their in vitro release pattern and for dark and photo-cytotoxic anticancer activity on breast cancer cell line in comparison to free CUR.. Evaluation tests showed the appropriateness of NLCs prepared from glyceryl monooleate and Geleol™ helped choosing two optimized formulae, PE3 and GE3. PE3 (prepared using glyceryl monooleate) showed enhanced release rates compared to GE3 (prepared from Geleol) and superior cytotoxic anticancer activity compared to both GE3 and free CUR under both light and dark conditions. The small mean PS, spherical shape as well as the negative ZP enhanced the internalization of the NLCs within cells. Modulation and inhibition of P-glycoprotein expression by glyceryl monooleate synergized the cytotoxic activity of CUR.. CUR loading in NLCs enhanced its cell penetration and cytotoxic anticancer properties both in dark and in light conditions.

Topics: Breast Neoplasms; Cell Survival; Curcumin; Drug Carriers; Drug Liberation; Female; Humans; Lipids; MCF-7 Cells; Nanostructures; Oleic Acids; Olive Oil; Particle Size; Photochemotherapy; Static Electricity

This is a demand-based infodemiology study using the Google Trends and AdWords tools to illustrate infodemiology's potential use in rheumatology. The study investigates three questions in North American countries: (1) What terms associated with "rheumatology" and "arthritis" do people search for on Google? (2) What is the search volume for disease-modifying antirheumatic drugs (DMARDs)? and (3) What is the search volume for the term "arthritis" compared with for "hepatitis C" and "breast cancer"?. We conducted independent searches by country and search term for 2015-2017. Seventeen DMARDs were searched for 2015 through May 2018, with the turmeric remedy included for comparison. Data were exported to Excel for further analysis, adjusted by country population, and expressed as searches per 100,000 inhabitants (SpTh).. There were approximately 550 associated terms for "arthritis" in each country, and 5679 SpTh for DMARDs across the three countries. Searches for turmeric numbered slightly lower than for all DMARDs together in Canada and the USA, but were 70% higher in Mexico. Turmeric was also searched four times more than the most-searched biological DMARD in Canada and the USA, and 60 times more in Mexico. Arthritis was more commonly searched for in Canada than hepatitis C and breast cancer, but hepatitis C was highest in the USA and breast cancer in Mexico. Monthly trends did not show expected peaks associated with arthritis awareness campaigns.. Infodemiology provides preliminary information that could help in generating hypotheses, assessing health-care interventions, or even in providing patient-centered care.

Topics: Antirheumatic Agents; Arthritis; Breast Neoplasms; Canada; Consumer Health Information; Curcuma; Epidemiology; Health Services; Hepatitis C; Humans; Information Seeking Behavior; Mexico; Rheumatology; Search Engine; United States

Curcumin has shown promising inhibitory activity against HER-2-positive tumor cells in vitro but suffers from poor oral bioavailability in vivo. Our lab has previously developed a polymeric microparticle formulation for sustained delivery of curcumin for chemoprevention. The goal of this study was to examine the anticancer efficacy of curcumin-loaded polymeric microparticles in a transgenic mouse model of HER-2 cancer, Balb-neuT. Microparticles were injected monthly, and mice were examined for tumor appearance and growth. Initiating curcumin microparticle treatment at 2 or 4 weeks of age delayed tumor appearance by 2-3 weeks compared to that in control mice that received empty microparticles. At 12 weeks, abnormal (lobular hyperplasia, carcinoma in situ, and invasive carcinoma) mammary tissue area was significantly decreased in curcumin microparticle-treated mice, as was CD-31 staining. Curcumin treatment decreased mammary VEGF levels significantly, which likely contributed to slower tumor formation. When compared to saline controls, however, blank microparticles accelerated tumorigenesis and curcumin treatment abrogated this effect, suggesting that PLGA microparticles enhance tumorigenesis in this model. PLGA microparticle administration was shown to be associated with higher plasma lactic acid levels and increased activation of NF-κΒ. The unexpected side effects of PLGA microparticles may be related to the high dose of the microparticles that was needed to achieve sustained curcumin levels in vivo. Approaches that can decrease the overall dose of curcumin (for example, by increasing its potency or reducing its clearance rate) may allow the development of sustained release curcumin dosage forms as a practical approach to cancer chemoprevention.

Topics: Animals; Anticarcinogenic Agents; Breast Neoplasms; Cell Proliferation; Curcumin; Cytokines; Delayed-Action Preparations; Disease Models, Animal; Drug Carriers; Female; Genes, erbB-2; Lactic Acid; Mice, Inbred BALB C; Mice, Transgenic; Neovascularization, Pathologic; NF-kappa B; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Vascular Endothelial Growth Factor A

The study was aimed at investigating the synergistic inhibitory effect of unique combinational regimen of nanocapsulated Metformin (Met) and Curcumin (Cur) against T47D breast cancer cells. For this purpose, Met and Cur were co-encapsulated in PEGylated PLGA nanoparticles (NPs) and evaluated for their therapeutic efficacy. The morphology and dynamic light scattering (DLS) analyses were carried out to optimize the nanoformulations. Drug release study was performed using dialysis method and then the cytotoxic and inhibitory effect of individual and combined drugs on expression level of hTERT in T47D breast cell line were evaluated using MTT assay and qPCR, respectively. The results showed that free drugs and formulations exhibited a dose-dependent cytotoxicity against T47D cells and especially, Met-Cur-PLGA/PEG NPs had more synergistic antiproliferative effect and significantly arrested the growth of cancer cells than the other groups (p < .05). Real-time PCR results revealed that Cur, Met and combination of Met-Cur in free and encapsulated forms inhibited hTERT gene expression. It was found that Met-Cur-PLGA/PEG NPs in relative to free combination could further decline hTERT expression in all concentration (p < .05). Taken together, our study demonstrated that Met-Cur-PLGA/PEG NPs based combinational therapy holds promising potential towards the treatment of breast cancer.

Topics: Breast Neoplasms; Capsules; Cell Line, Tumor; Cell Proliferation; Curcumin; Drug Carriers; Drug Liberation; Drug Synergism; Gene Expression Regulation, Neoplastic; Humans; Metformin; Nanoparticles; Particle Size; Polyesters; Polyethylene Glycols; Telomerase

The anti-cancer potential of curcumin, a natural NFκβ inhibitor, has been reported extensively in breast, lung and other cancers. In vitro and in vivo studies indicate that the therapeutic efficacy of curcumin is enhanced when formulated in a nanoparticulate carrier. However, the mechanism of action of curcumin at the molecular level in the hypoxic tumour micro-environment is not fully understood. Hence, the aim of our study was to investigate the mechanism of action of curcumin formulated as nanoparticles in in vitro models of breast and lung cancer under an hypoxic microenvironment.. Biodegradable poly(lactic-co-glycolic acid) PLGA nanoparticles (NP), loaded with curcumin (cur-PLGA-NP), were fabricated using a solvent evaporation technique to overcome solubility issues and to facilitate intracellular curcumin delivery. Cytotoxicity of free curcumin and cur-PLGA-NP was evaluated in MDA-MB-231 and A549 cell lines using migration, invasion and colony formation assays. All treatments were performed under an hypoxic micro-environment and whole cell lysates from controls and test groups were used to determine the expression of HIF-1α and p65 levels using ELISA assays.. A ten-fold increase in solubility, three-fold increase in anti-cancer activity and a significant reduction in the levels of cellular HIF-1α and nuclear p65 (Rel A) were observed for cur-PLGA-NP, when compared to free curcumin.. Our findings indicate that curcumin can effectively lower the elevated levels of HIF-1α and nuclear p65 (Rel A) in breast and lung cancer cells under an hypoxic tumour micro-environment when delivered in nanoparticulate form. This applied means of colloidal delivery could explain the improved anti-cancer efficacy of curcumin and has further potential applications in enhancing the activity of anti-cancer agents of low solubility.

Topics: A549 Cells; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Curcumin; Drug Carriers; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Lactic Acid; Lung Neoplasms; Nanoparticles; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Polymers; Solubility; Transcription Factor RelA

Hand-foot syndrome (HFS) is common and frequently occurs in the first cycle of treatment in approximately 40% to 50% of patients who receive capecitabine. Turmeric (Curcuma longa) is a plant used in Ayurvedic medicine with clinical activity in various inflammatory conditions. Our objective was to evaluate whether turmeric was active for the prevention of capecitabine-induced HFS. We included patients older than 18 years of age without previous exposure to capecitabine who were scheduled to receive this medication. Before starting treatment, after three weeks and at the end of six weeks, we evaluated dermatologic toxicity, conducted quality-of-life questionnaires (EORTC-QLQC30 and DLQI) and collected serum inflammatory biomarkers (inerleukin-6 (IL-6), tumor necrosis factor-a (TNF-a), C-reactive protein (CRP), and albumin). We administered turmeric at a dose of 4 g/day (2 pills 12 hours apart) starting at the beginning of capecitabine treatment and lasting six weeks. We included 40 patients whose mean age was 62 years. Most were female (80%), 52% had breast cancer, and 47.5% had GI tumors. After the first cycle of capecitabine treatment, we observed that 11 of 40 patients developed HFS (27.5%; 95% CI [15, 42]), whereas four patients developed HFS equal or superior to grade 2 (10%; 95% CI [3.3, 23]). We did not find any correlations between the inflammatory markers tested and HFS. We show that turmeric combined with capecitabine seems to produce a lower rate of HFS, especially grade 2 or higher. These findings need to be reproduced in larger controlled studies.

Topics: Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Breast Neoplasms; C-Reactive Protein; Capecitabine; Curcuma; Curcumin; Female; Gastrointestinal Neoplasms; Hand-Foot Syndrome; Humans; Interleukin-6; Male; Middle Aged; Phytotherapy; Pilot Projects; Quality of Life; Serum Albumin; Surveys and Questionnaires; Tumor Necrosis Factor-alpha

Topics: Androstadienes; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma, Ductal, Breast; Curcumin; Dietary Supplements; Everolimus; Female; Humans; Middle Aged

Breast cancer is a prevalent cancer in female. This study aims to investigate the therapeutic potential and mechanism of curcumin in breast cancer.. After cultivation, human breast cancer cells (MCF-7 cells) were treated with 0.1% (v/v) 15 µmol/ml curcumin-dimethylsulfoxide solution and 0.1% (v/v) dimethylsulfoxide, respectively, at 37 °C and 5% CO. After DEGs screening, 347 DEGs were identified. Up-regulated DEGs were enriched in 14 functions and 3 pathways, and associated with 12 drugs. Down-regulated DEGs were enriched in 14 functions and 9 pathways, and associated with 14 drugs. Moreover, 5 DEGs were associated with breast cancer, including PGAP3, MAP3K1, SERPINE1, PON2, and GSTO2. PPI network was constructed, and the top DEGs were FOS, VIM, FGF2, MAPK1, SPARC, TOMM7, PSMB10, TCEB2, SOCS1, COL4A1, UQCR11, SERPINE1, and ISG15.. Curcumin might have therapeutic potential in breast cancer through regulating breast cancer-related genes, including SERPINE1, PGAP3, MAP3K1, MAPK1, GSTO2, VIM, SPARC, and FGF2. However, validations are required.

Topics: Antineoplastic Agents; Biomarkers, Tumor; Breast Neoplasms; Computational Biology; Curcumin; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; High-Throughput Nucleotide Sequencing; Humans; Prognosis; Protein Interaction Maps; Tumor Cells, Cultured

Despite advances in medical technology, radiation dermatitis occurs in 95% of patients receiving radiation therapy (RT) for cancer. Currently, there is no standard and effective treatment for the prevention or control of radiation dermatitis. The goal of the study was to determine the efficacy of oral curcumin, one of the biologically active components in turmeric, at reducing radiation dermatitis severity (RDS) at the end of RT, using the RDS scale, compared to placebo.. This was a multisite, randomized, double-blinded, placebo-controlled trial of 686 breast cancer patients. Patients took four 500-mg capsules of placebo or curcumin three times daily throughout their prescribed course of RT until 1 week post-RT.. A total of 686 patients were included in the final analyses (87.5% white females, mean age = 58). Linear mixed-model analyses demonstrated that curcumin did not reduce radiation dermatitis severity at the end of RT compared to placebo (B (95% CI) = 0.044 (- 0.101, 0.188), p = 0.552). Fewer curcumin patients with RDS > 3.0 suggested a trend toward reduced severity (7.4 vs. 12.9%, p = 0.082). Patient-reported changes in pain, symptoms, and quality of life were not statistically significant between arms.. Oral curcumin did not significantly reduce radiation dermatitis severity compared to placebo. The skin rating variation and broad eligibility criteria could not account for the undetectable therapeutic effect. An objective measure for radiation dermatitis severity and further exploration for an effective treatment for radiation dermatitis is warranted.

Topics: Administration, Oral; Breast Neoplasms; Curcumin; Double-Blind Method; Female; Humans; Middle Aged; Quality of Life; Radiodermatitis; Treatment Outcome

Most breast tumours are heterogeneous and not only contain the bulk of differentiated tumour cells but also a small population of highly tumorigenic and intrinsically drug-resistant cancer stem cells (CSCs). Herein, a pH-sensitive nanoparticle with simultaneous encapsulation of curcumin and doxorubicin (CURDOX-NPs) was prepared by using monomethoxy (polyethylene glycol)-b-P (D,L-lactic-co-glycolic acid)-b-P (L-glutamic acid) polymer to simultaneously target the differentiated tumor cells and CSCs. CURDOX-NPs had a mean diameter of 107.5 nm and zeta potential of -13.7 mV, determined by DLS. Drug-loading efficiency for curcumin and doxorubicin was reaching to 80.30% and 96.2%, respectively. Moreover, a cascade sustained-release profiles with the faster release of CUR followed by a slower release of DOX was observed in normal pH7.4 condition. Moreover, a pH-sensitive release profile for each cargo was seen in pH5.0 condition. The anti-tumour effect of CURDOX-NPs on CSCs-enriching MCF-7/ADR mammospheres was confirmed by in vitro. Moreover, a significant regression of tumour growth after treatment with CURDOX-NPs was also observed in Xenograft mice model. The percentage of CSCs in tumour significantly decreased from 39.9% in control group to 6.82% after treatment with CURDOX-NPs. The combinational delivery of CUR and DOX may a potentially useful therapeutic strategy for refractory breast cancer.

Topics: Animals; Breast Neoplasms; Capsules; Cell Proliferation; Curcumin; Doxorubicin; Drug Carriers; Drug Liberation; Humans; Hydrogen-Ion Concentration; MCF-7 Cells; Mice; Nanoparticles; Particle Size; Polyesters; Polyethylene Glycols; Polyglutamic Acid; Xenograft Model Antitumor Assays

Cancer stem cells (CSCs) play an essential role in the progression of many tumors. Sonic hedgehog (Shh) and Wnt/β-catenin pathways are crucial in maintaining the stemness of CSCs. Curcumin has been shown to possess anticancer activity. However, the interventional effect of curcumin on breast CSCs has not been elucidated. In the present study, we investigated the role of Shh and Wnt/β-catenin pathway in curcumin inhibition of breast CSCs. We showed that the levels of breast CSCs markers were significantly elevated in SUM159 and MCF7 sphere-forming cells. We further illustrated that curcumin effectively decreased breast CSCs activity by inhibiting tumor sphere formation, decreasing breast CSCs markers (CD44, ALDH1A1, Nanog, and Oct4), as well as inhibiting proliferation and inducing apoptosis. Moreover, we showed that downregulation of Shh and Wnt/β-catenin activity resulted in breast CSCs inhibition; curcumin exerted an inhibitory effect on breast CSCs by suppressing both Shh and Wnt/β-catenin pathways. Taken together, these results indicated curcumin inhibition of breast CSCs by downregulation of Shh and Wnt/β-catenin pathways. Findings from this study could provide new insights into the potential therapeutic application of curcumin in breast CSCs elimination and cancer intervention.

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Curcumin; Down-Regulation; Female; Hedgehog Proteins; Humans; MCF-7 Cells; Neoplastic Stem Cells; Wnt Signaling Pathway

To estimate the clinical impact of pharmacokinetic modulation via breast cancer resistance protein (BCRP), in vivo approaches in nonclinical settings are desired in drug development. Clinical observation has identified curcumin as a promising candidate for in vivo selective BCRP inhibition, in addition to several well known inhibitors, such as lapatinib and pantoprazole. This study aimed to confirm the inhibitory efficacy of curcumin on gastrointestinal BCRP function in cynomolgus monkeys and to perform comparisons with lapatinib and pantoprazole. Oral area under the plasma concentration-time curve (AUC) and bioavailability of well known BCRP (sulfasalazine and rosuvastatin), P-glycoprotein (fexofenadine, aliskiren, and talinolol), and CYP3A (midazolam) substrates were investigated in the presence and absence of inhibitors. Oral exposures of sulfasalazine and rosuvastatin were markedly elevated by curcumin with minimal changes in systemic clearance, whereas pharmacokinetic alterations after fexofenadine, aliskiren, and talinolol oral exposure were limited. Curcumin increased oral midazolam exposure without affecting systemic clearance, presumably owing to partial inhibition of intestinal CYP3A. Lapatinib increased the oral AUC for sulfasalazine to a greater extent than curcumin did, whereas pantoprazole had a smaller effect. However, lapatinib also exerted significant effects on fexofenadine, failed to selectively discriminate between BCRP and P-glycoprotein inhibition, and had an effect on oral midazolam exposure comparable with that of curcumin. Thus, pharmacokinetic evaluation in monkeys demonstrated that pretreatment with curcumin as an in vivo selective BCRP inhibitor was more appropriate than pretreatment with lapatinib and pantoprazole for the assessment of the impact of BCRP on gastrointestinal absorption in nonrodent models.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; Biological Availability; Breast Neoplasms; Caco-2 Cells; Cell Line, Tumor; Curcumin; Cytochrome P-450 CYP3A; Female; Humans; Intestinal Absorption; Intestinal Mucosa; Intestines; Lapatinib; Macaca fascicularis; Male; Midazolam; Neoplasm Proteins; Pantoprazole; Quinazolines; Rosuvastatin Calcium; Sulfasalazine; Terfenadine

Liquid lipid nanocapsules (LLN) represent a promising new generation of drug-delivery systems. They can carry hydrophobic drugs in their oily core, but the composition and structure of the surrounding protective shell determine their capacity to survive in the circulatory system and to achieve their goal: penetrate tumor cells. Here, we present a study of LLN covered by the protein human serum albumin (HSA) and loaded with curcumin as a hydrophobic model drug. A cross-linking procedure was performed to further strengthen the protective protein layer. Physicochemical properties and release kinetics of the nanocapsules were investigated, and cellular uptake and killing capacity were evaluated on the human breast-cancer line MCF-7. The nanocapsules exhibited a half maximal inhibitory concentration (IC

Topics: Breast Neoplasms; Cell Proliferation; Cell Survival; Coumarins; Curcumin; Drug Liberation; Endocytosis; Female; Humans; Lipids; MCF-7 Cells; Nanocapsules; Serum Albumin; Thiazoles

Topics: A549 Cells; Antineoplastic Agents; Apoptosis; Aurora Kinase A; Breast Neoplasms; Cell Cycle Proteins; Cell Line; Cell Survival; Curcumin; Cyclin B1; Cyclin-Dependent Kinase Inhibitor p21; Drug Combinations; Estrogens; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Humans; MCF-7 Cells; Mitosis; Polo-Like Kinase 1; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Resveratrol; Stilbenes

Nanoassembly (NA) based on a D-α-tocopherol succinate (αTS) conjugated lysozyme (Lys) (Lys-αTS) was fabricated for tumor-selective delivery of curcumin (CUR) for breast cancer therapy. Lys and αTS were used as a biocompatible enzyme and a hydrophobic residue, respectively, for the preparation of nanocarriers in this study. Compared with CUR-loaded cross-linked Lys (c-Lys/CUR) NA, Lys-αTS/CUR NA exhibited a smaller hydrodynamic size (213 nm mean diameter), a narrower size distribution, and a more spherical shape. Sustained drug release was observed from the Lys-αTS/CUR NA for five days at a normal physiological pH (pH 7.4). The developed Lys-αTS/CUR NA showed enhanced cellular accumulation, antiproliferative effects, and apoptotic efficacies in MDA-MB-231 human breast adenocarcinoma cells. According to the results of optical imaging test in the MDA-MB-231 tumor-bearing mouse models, the Lys-αTS/CUR NA-injected group exhibited a more tumor-selective accumulation pattern, rather than being distributed in the normal tissues and organs. The observed tumor targetability of Lys-αTS/CUR was further studied, which revealed improved in vivo anticancer activities (better inhibition of tumor growth and induction of apoptosis in the tumor tissue) after an intravenous administration in the MDA-MB-231 tumor-bearing mouse models. All these results indicate that the newly developed enzyme-based nanocarrier, the Lys-αTS NA, can be a promising candidate for the therapy of breast cancers.

Topics: alpha-Tocopherol; Animals; Antineoplastic Agents; Breast Neoplasms; Chickens; Curcumin; Female; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Muramidase; Nanoparticles; Optical Imaging; Tumor Burden; Xenograft Model Antitumor Assays

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Proliferation; Curcumin; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Female; Humans; Molecular Structure; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase C-theta; Signal Transduction; Structure-Activity Relationship; TOR Serine-Threonine Kinases; Tumor Cells, Cultured

Denderimer-modified magnetic nanoparticles are a promising drug delivery nanosystem which can improve the therapeutic efficacy of chemotherapy drugs and can also be beneficial as magnetic resonance (MR) images contrast agent. The present study introduces the preparation and characterization of the potential therapeutic efficiency of curcumin (CUR)-loaded denderimer-modified citric acid coated Fe

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Survival; Citric Acid; Contrast Media; Curcumin; Delayed-Action Preparations; Dendrimers; Drug Carriers; Drug Compounding; Drug Liberation; Drug Screening Assays, Antitumor; Female; Humans; Hydrogen-Ion Concentration; Magnetite Nanoparticles; MCF-7 Cells; Polyethylene Glycols

Here we explored the antitumor-activity of novel-formulated-form of curcumin (phytosomal-encapsulated-curcumin) or in combination with 5-FU in breast cancer. The antiproliferative activity was assessed in 2D and 3-dimensional cell-culture-model. The migratory-behaviors of the cells were determined by migration assay. The expression levels of CyclinD1,GSK3a/b, P-AMPK, MMP9, and E-cadherin were studied by qRT-PCR and/or Western blotting. The anti-inflammatory of nano-curcumin was assessed, while antioxidant activity was evaluated by malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and total thiols (T-SH). To understand dynamic behavior of genes, we reconstructed a Boolean network, while the robustness of this model was evaluated by Hamming distance. phytosomal-curcumin suppressed cell-growth followed by tumor-shrinkage in 3D model through perturbation of AMP-activated protein kinase. Curcumin reduced the invasiveness of MCF-7 through perturbation of E-cadherin. Moreover, phytosomal-curcumin inhibited the tumor growth in xerograph model. Histological staining of tumor tissues revealed vascular disruption and RBC extravasation, necrosis, tumor stroma, and inflammation. Co-treatment of curcumin and 5-FU reduced the lipid-peroxidation and increased MDA/SOD level. Of note, curcumin reduced cyclinD-expression in breast cancer cell treated with thrombin, and activates AMPK in a time-dependent manner. Also suppression of AMPK abrogated inhibitory effect of phytosomal-curcumin on thrombin-induced cyclin D1 over-expression, suggesting that AMPK is essential for anti-proliferative effect of this agent in breast cancer. Our finding demonstrated that phytosomal-curcumin antagonizes cell growth and migration, induced by thrombin through AMP-Kinase in breast cancer, supporting further-investigations on the therapeutic potential of this novel anticancer agent in treatment of breast cancer.

Topics: AMP-Activated Protein Kinases; Animals; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Movement; Cell Proliferation; Curcumin; Drug Compounding; Female; Gene Expression Regulation, Neoplastic; Hemostatics; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Thrombin; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

This study was focused on developing a drug carrier system composed of a polymer containing hydroxyapatite (HAp) shell and a magnetic core of iron oxide nanoparticles. Doxorubicin and/or curcumin were loaded into the carrier via a simple diffusion deposition approach, with encapsulation efficiencies (EE) for curcumin and doxorubicin of 93.03 ± 0.3% and 97.37 ± 0.12% respectively. The co-loading of curcumin and doxorubicin led to a total EE of 76.02 ± 0.48%. Release studies were carried out at pH 7.4 and 5.3, and revealed a greater extent of release at pH 5.3, showing the formulations to have potential applications in tumor microenvironments. Cytotoxicity assays, fluorescence imaging and flow cytometry demonstrated that the formulations could effectively inhibit the growth of MCF-7 (breast) and HEpG2 (liver) cancer cells, being more potent than the free drug molecules both in terms of dose and duration of action. Additionally, hemolysis tests and cytotoxicity evaluations determined the drug-loaded carriers to be non-toxic towards non-cancerous cells. These formulations thus have great potential in the development of new cancer therapeutics.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Proliferation; Curcumin; Doxorubicin; Drug Carriers; Durapatite; Female; Ferric Compounds; Flow Cytometry; Hemolysis; Hep G2 Cells; Humans; Hydrogen-Ion Concentration; Hydrophobic and Hydrophilic Interactions; Liver Neoplasms; Male; MCF-7 Cells; Nanoparticles; Optical Imaging; Polymers; Rats, Wistar

Topics: Administration, Cutaneous; Animals; Antineoplastic Agents; Breast Neoplasms; Cell Survival; Curcumin; Drug Delivery Systems; Female; Humans; Male; MCF-7 Cells; Mice; Nanoparticles; Particle Size; Skin; Skin Absorption

Curcumin is known to possess various biological functions, including anti-inflammatory, antioxidative, and anti-cancer activities. Natural killer (NK) cells are large lymphocytes that directly kill cancer cells. However, many aggressive cancers, including breast cancer, were reported to escape the successful killing of NK cells in a tumor microenvironment. In this study, we investigated the anti-cancer effect of curcumin in coculture of human breast carcinoma MDA-MB-231 and NK (NK-92) cells. We found that curcumin had an immune-stimulatory effect on NK-92 by increasing the surface expression of the CD16⁺ and CD56

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line; Coculture Techniques; Curcumin; Humans; Immunologic Factors; Killer Cells, Natural; Models, Biological

In order to metastasize, tumor cells need to migrate and invade the surrounding tissues. It is important to identify compound(s) capable of disrupting the metastasis of invasive cancer cells, especially for hindering invadopodia formation, so as to provide anti-metastasis targeted therapy. Invadopodia are thought to be specialized actin-rich protrusions formed by highly invasive cancer cells to degrade the extracellular matrix (ECM). A curcuminoid analogue known as 2,6-bis-(4-hydroxy-3-methoxybenzylidine)cyclohexanone or BHMC has shown good potential in inhibiting inflammation and hyperalgesia. It also possesses an anti-tumor effects on 4T1 murine breast cancer cells in vivo. However, there is still a lack of empirical evidence on how BHMC works in preventing human breast cancer invasion. In this study, we investigated the effect of BHMC on MDA-MB-231 breast cancer cells and its underlying mechanism of action to prevent breast cancer invasion, especially during the formation of invadopodia. All MDA-MB-231 cells, which were exposed to the non-cytotoxic concentrations of BHMC, expressed the proliferating cell nuclear antigen (PCNA), which indicate that the anti-proliferative effects of BHMC did not interfere in the subsequent experiments. By using a scratch migration assay, transwell migration and invasion assays, we determined that BHMC reduces the percentage of migration and invasion of MDA-MB-231 cells. The gelatin degradation assay showed that BHMC reduced the number of cells with invadopodia. Analysis of the proteins involved in the invasion showed that there is a significant reduction in the expressions of Rho guanine nucleotide exchange factor 7 (β-PIX), matrix metalloproteinase-9 (MMP-9), and membrane type 1 matrix metalloproteinase (MT1-MMP) in the presence of BHMC treatment at 12.5 µM. Therefore, it can be postulated that BHMC at 12.5 µM is the optimal concentration for preventing breast cancer invasion.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Curcumin; Cyclohexanones; Female; Gene Expression Regulation, Neoplastic; Humans; Matrix Metalloproteinase 14; Matrix Metalloproteinase 9; Proliferating Cell Nuclear Antigen; Rho Guanine Nucleotide Exchange Factors

Despite positive results obtained from anticancer activities of curcumin, there are some obstacles that limit its use as an anticancer agent.. Different methods such as employing the dendrosomal curcumin (DNC) were examined to overcome such problems. There is increasing evidence representing long non-coding RNAs play important roles in biological processes. In this study, we focused on the roles of GAS5 in the anti-cancer effects of DNC on breast cancer.. We used several methods including MTT assay, apoptosis assay, cell cycle analysis, transwell migration assay and RT-PCR.. We observed a significant increase in the expression of Tusc7, and GAS5 genes with DNC treatment of MCF7, MDA-MB231, and SKBR3 cells. Also, the combination of GAS5 down-regulation and DNC treatment showed lower percentages of apoptotic cells and a higher level of penetration through the membrane compared with DNC treatment alone. Furthermore, DNC induced a significant increase in the number of cells in sub G1/G1 phase and a decrease in the G2/M phase of the cell cycle. But, after GAS5 down-regulation alone opposite results was observed compared to DNC.. We observed that GAS5 down-regulation can suppress many aspects of DNC anti-cancer effects in breast cancer cells, it seems that co-treatment with DNC and GAS5 over-expression may provide a clinically useful tool for drug-resistance breast cancer cells.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Breast Neoplasms; Cell Cycle; Cell Line, Tumor; Curcumin; Down-Regulation; Female; G1 Phase; Gene Expression Regulation, Neoplastic; Humans; MCF-7 Cells; Nanoparticles; RNA, Long Noncoding

Codelivery of chemo-sensitizers with chemotherapeutics using combo nanomedicine is a promising platform for overcoming chemoresistance in breast cancer. However, tumor accumulation of nano-carriers based on enhanced permeability and retention (EPR) effect is confounded by heterogeneity in tumor microenvironment. Adsorption of protein corona on surface of nanoparticle boost up clearance by reticulo-endothelial system. In this study, a surface functionalized magnetic nanocomposite (NC) for codelivery of doxorubicin (DOX) and curcumin (CUR) is developed. NCs were coated with hydroxyapatite and were also cross linked with β-cyclodextrin. NCs efficiently encapsulated DOX and CUR. Release of CUR and DOX were in a sustained pH-depended pattern. β-cyclodextrin functionalization reduced protein corona according sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) analysis. As shown by flowcytometric and confocal microscopy analyses, NCs internalized efficiently by human breast carcinoma cells MCF-7 and adriamycin resistant MCF-7 (MCF-7/adr) cells. 3-(4,5-Dimethyl-thiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) test demonstrated superior cytotoxicity of DOX-CUR loaded NCs. Anti-tumor efficacy analyses confirmed reduction in relative tumor volume size (RTV%) compared to control group. Western blot analyses demonstrated marginal CUR mediated P-glycoprotein (P-gp) down regulation. DOX-CUR loaded NCs efficiently accumulated into the tumor via external magnet guidance. Nevertheless, the increased tumor accumulation did not correlate with pharmacologic responses such as RTV% and significant superiority over free DOX was not observed.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; beta-Cyclodextrins; Biocompatible Materials; Biological Transport; Breast Neoplasms; Curcumin; Doxorubicin; Drug Carriers; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Humans; Hydrogen-Ion Concentration; Magnets; MCF-7 Cells; Mice; Mice, Inbred BALB C; Nanomedicine; Nanoparticles

Human breast cell lines are often characterized based on the expression of the cell surface markers CD44 and CD24. CD44 is a type I transmembrane glycoprotein that regulates cell adhesion and cell-cell, as well as cell-extracellular matrix interactions. CD24 is expressed in benign and malignant solid tumors and is also involved in cell adhesion and metastasis. The aim of the present study was to investigate the effects of curcumin on the surface expression of CD44 and CD24 in breast epithelial cell lines. An established breast cancer model derived from the MCF-10F cell line was used. The results revealed that curcumin decreased CD44 and CD24 gene and protein expression levels in MCF-10F (normal), Alpha5 (premalignant) and Tumor2 (malignant) cell lines compared with the levels in their counterpart control cells. Flow cytometry revealed that the CD44+/CD24+ cell subpopulation was greater than the CD44+/CD24- subpopulation in these three cell lines. Curcumin increased CD44+/CD24+ to a greater extent and decreased CD44+/CD24- subpopulations in the normal MCF-10F and the pre-tumorigenic Alpha5 cells, but had no significant effect on Tumor2 cells compared with the corresponding control cells. Conversely, curcumin increased CD44 and decreased CD24 gene expression in MCF-7 breast cancer cells, and decreased CD44 gene expression in MDA-MB-231 cell line, while CD24 was not present in these cells. Curcumin did not alter the CD44+/CD24+ or CD44+/CD24- subpopulations in the MCF-7 cell line. However, it increased CD44+/CD24+ and decreased CD44+/CD24- subpopulations in MDA-MB-231 cells. In breast cancer specimens from patients, normal tissues were negative for CD44 and CD24 expression, while benign lesions were positive for both markers, and malignant tissues were found to be negative for CD44 and positive for CD24 in most cases. In conclusion, these results indicated that curcumin may be used to improve the proportion of CD44+/CD24+ cells and decrease the proportion of CD44+/CD24- cells. Therefore, it may be suggested that curcumin decreased cancerous types of breast cells.

Topics: Biomarkers, Tumor; Breast Neoplasms; CD24 Antigen; Cell Line, Tumor; Curcumin; Female; Gene Expression Regulation, Neoplastic; Humans; Hyaluronan Receptors; MCF-7 Cells

Solid lipid nanoparticles (SLNs) represent an affordable, easily scalable, stable and biocompatible drug delivery system with a high drug to lipid ratio which also improves solubility of poorly soluble drugs.. SLNs were developed by using glyceryl monostearate as the single lipid in the presence of surfactant Poloxamer 188 and evaluated the efficiency of SLNs to load the therapeutic cargo, curcumin (CUR).. The nano-formulation was optimized by Quality by Design approach to understand the effect of various process parameters on various quality attributes, including drug loadability, particle size and polydispersity. The nanoparticles were characterized using Differential scanning calorimetry (DSC), Fourier Transform Infra-red Spectroscopy (FT-IR) and X-Ray Diffraction (XRD) analysis. These novel SLNs were evaluated for in-vitro anticancer activity using breast adenocarcinoma cells (MDA-MB-231).. The optimized formulation had a particle size of 226.802±3.92 nm with low polydispersity index of 0.244±0.018. The % encapsulation of CUR into SLNs was found to be 67.88±2.08 %. DSC, FT-IR and XRD confirmed that the CUR was encapsulated stably into the lipid matrix, thereby improving the solubility of the drug. CUR-SLN showed sustained drug release in comparison to the free CUR solution. CUR-SLNs exhibited higher cellular uptake in human breast adenocarcinoma cells compared to free CUR at both 1 and 4 h time points. CUR-SLNs demonstrated decreased cell viability (43.97±1.53%) compared to free CUR (59.33±0.95%) at a concentration of 50 µg/mL after 24 h treatment. Furthermore, the treatment of MDA-MB-231 cells with CUR-SLNs for 24 h induced significantly higher apoptosis (37.28±5.3%) in cells compared to the free CUR (21.06±0.97%).. The results provide a strong rationale for further exploration of the newly developed CUR-SLN to be utilized as a potent chemotherapeutic agent in cancer therapy.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Proliferation; Curcumin; Drug Design; Drug Screening Assays, Antitumor; Female; Glycerides; Humans; Lipids; Nanoparticles; Particle Size; Surface Properties; Tumor Cells, Cultured

Curcumin is assumed to be a plant-derived therapeutic drug that triggers apoptotic cell death in vitro and in vivo by affecting different molecular targets such as NF-κB. Phase I/II trial of curcumin alone or with chemotherapeutic drugs has been accomplished in pancreatic, colon, prostate and breast cancer cases. Recently, autocrine growth hormone (GH) signaling-induced cell growth, metastasis and drug resistance have been demonstrated in breast cancer. In this study, our aim was to investigate the potential therapeutic effect of curcumin by evaluating the molecular machinery of curcumin-triggered apoptotic cell death via focusing on NF-κB signaling and polyamine (PA) metabolism in autocrine GH-expressing MCF-7, MDA-MB-453 and MDA-MB-231 breast cancer cells. For this purpose, a pcDNA3.1 (+) vector with a GH gene insert was transfected by a liposomal agent in all breast cancer cells and then selection was conducted in neomycin (G418) included media. Autocrine GH-induced curcumin resistance was overcome in a dose-dependent manner and curcumin inhibited cell proliferation, invasion-metastasis and phosphorylation of p65 (Ser536), and thereby partly prevented its DNA binding activity in breast cancer cells. Moreover, curcumin induced caspase-mediated apoptotic cell death by activating the PA catabolic enzyme expressions, which led to generation of toxic by-products such as H

Topics: Antineoplastic Agents; Apoptosis; Autocrine Communication; Breast Neoplasms; Cell Movement; Cell Survival; Curcuma; Curcumin; Epithelial-Mesenchymal Transition; Female; G2 Phase Cell Cycle Checkpoints; Human Growth Hormone; Humans; M Phase Cell Cycle Checkpoints; MCF-7 Cells; Neoplasm Metastasis; NF-kappa B; Plant Extracts; Polyamines

The antitumor applications of curcumin (CUR) are limited because of its low water solubility, poor stability, and low bioavailability. We developed novel nanocarrier systems for tumour targeting and controlled CUR release and evaluated their therapeutic efficacy.. The surface of mesoporous silica nanoparticles (MSN) was modified with hyaluronan (HA) or polyethyleneimine-folic acid (PEI-FA) via disulfide bonds. The capacity of the resultant nanocarriers (MSN-HA and MSN-PEI-FA, respectively) for CUR delivery was evaluated in a breast cancer cell line and a mouse xenograft model.. MSN/CUR-PEI-FA and MSN/CUR-HA were cytotoxic to MDA-MB-231 breast cancer cells. Both formulations showed an enhanced cellular uptake compared with that of a non-targeted nanocarrier, with a greater cellular uptake of FA-modified nanoparticles than that of HA-modified nanoparticles. Accordingly, MSN-PEI-FA showed more precise targeting and higher accumulation in tumours than did MSN-HA, as visualized by live imaging. Both types of nanoparticles had good biocompatibility and low toxicity, and MSN/CUR-PEI-FA inhibited the tumour growth to a greater degree than did free CUR. Thus, MSN/CUR-PEI-FA are a promising drug delivery system for the treatment of breast cancer.

Topics: Animals; Breast Neoplasms; Cell Cycle; Cell Survival; Curcumin; Drug Carriers; Drug Liberation; Humans; MCF-7 Cells; Mice; Nanoparticles; Oxidation-Reduction; Porosity; Rats; Silicon Dioxide; Xenograft Model Antitumor Assays

Many cancers, such as human breast cancer and lung cancer, easily metastasize to bones, leading to the formation of secondary tumors in advanced stages. On the basis of the CD44-targeted effect of oHA and the bone-targeted effect of ALN, we prepared a reduction-responsive, CD44 receptor-targeting and bone-targeting nanomicelle, called CUR-loaded ALN-oHA-S-S-CUR micelles. In this study, we aimed to evaluate the antitumor activity and bone-targeting ability of CUR-loaded ALN-oHA-S-S-CUR micelles. The in vivo experiment results showed that a larger number of micelles was gathered in the bone metastatic tumor tissue and reduced the bone destruction. The CUR-loaded ALN-oHA-S-S-CUR micelles markedly inhibited the tumor growth. So the CUR-loaded ALN-oHA-S-S-CUR micelles constitute a promising drug delivery system for bone tumor therapy.

Topics: Alendronate; Animals; Antineoplastic Agents; Bone Neoplasms; Breast Neoplasms; Cell Line, Tumor; Curcumin; Drug Carriers; Drug Liberation; Female; Humans; Hyaluronan Receptors; Hyaluronic Acid; Hydrogen-Ion Concentration; Mice; Mice, Nude; Micelles; Oxidation-Reduction; Particle Size; Polymers; Treatment Outcome; Xenograft Model Antitumor Assays

Background: Curcumin was shown to reduce epithelial-mesenchymal transition (EMT) markers in previous short\ term studies. This study was aimed to investigate the potential of curcumin in the prevention of EMT activation in\ MCF-7 cells induced by endoxifen. Methods: MCF-7 breast cancer cells were treated with Endoxifen 1000 nM+betaestradiol\ 1 nM with or without curcumin (8.5μM or 17 μM). Cells treated with dimethyl sulfoxide (DMSO) 0.001%\ were used as negative control. After 8 weeks of continuous treatment, the cells were counted, analyzed for mRNA\ E-cadherin, vimentin, TGF-β expression, total reactive oxygen species (ROS) and observed for morphological changes\ using confocal microscope and transmission electron microscope. Result: MCF-7 cell viability was increased in\ endoxifen + β-estradiol group. Cell viability was significantly decreased in curcumin 17 μM, but not in curcumin\ 8.5 μM group. Analysis of EMT markers at week 8 indicates that there were increase in vimentin and TGF-β mRNA\ expressions, while E-cadherin mRNA expressions and TGF-β1 protein concentrations were shown to decrease. The\ results showed that administration of curcumin in all the dose administered were incapable improving the expressions\ of vimentin, TGF-β1 and E-cadherin. There was a decrease in ROS concentration in curcumin treated cells (8.5 μM)\ while in curcumin 17 μM, ROS concentration was increased. Morphological observation using confocal microscope\ and TEM showed the presence of mesenchymal cells and adherens junction. Conclusion: endoxifen treatments for\ eight weeks resulted in upregulation of EMT markers and changes in morphology of MCF-7 breast cancer cells. The\ addition of curcumin did not prevent the activation of EMT.

Topics: Antigens, CD; Antineoplastic Agents; Breast Neoplasms; Cadherins; Curcumin; Epithelial-Mesenchymal Transition; Female; Humans; MCF-7 Cells; Signal Transduction; Tamoxifen; Transforming Growth Factor beta1

Curcumin (Cur) has been widely used in medicine, due to its antibacterial, anti-inflammatory, antioxidant, and antitumor effects. However, its clinic application is limited by its instability and poor solubility. In the present wok, curcumin was loaded into solid lipid nanoparticles (SLNs), in order to improve the therapeutic efficacy for breast cancer. The results measured using transmission electron microscopy (TEM) indicated that Cur-SLNs have a well-defined spherical shape; the size was about 40 nm with a negative surface charge. The drug loading and encapsulation efficiency in SLNs reached 23.38% and 72.47%, respectively. The Cur-SLNs showed a stronger cytotoxicity against SKBR3 cells. In vitro cellular uptake study demonstrated a high uptake efficiency of the Cur-SLNs by SKBR3 cells. Moreover, Cur-SLNs induced higher apoptosis in SKBR3 cells, compared to cells treated by free drug. In addition, Western blot analysis revealed that Cur-SLNs could promote the ratio of

Topics: Antineoplastic Agents; Apoptosis; Biomarkers; Breast Neoplasms; Cell Cycle; Cell Line, Tumor; Cell Movement; Cell Survival; Curcumin; Drug Carriers; Drug Compounding; Female; Humans; Lipids; Nanoparticles; Reactive Oxygen Species; Solubility; X-Ray Diffraction

Curcumin (Cur) is a naturally occurring anticancer drug isolated from the

Topics: Animals; Antineoplastic Agents; Apoptosis; Biocompatible Materials; Biological Availability; Breast Neoplasms; Bridged-Ring Compounds; Cell Line, Tumor; Cell Survival; Curcuma; Curcumin; Drug Delivery Systems; Humans; Imidazoles; Inhibitory Concentration 50; MCF-7 Cells; Melanoma; Molecular Structure; Organoplatinum Compounds; Paraquat; Rodentia; Solubility; STAT3 Transcription Factor; Water

Breast cancer is one of the major health issues confronting women; however, treatment with conventional chemotherapeutic drugs is limited. Currently, paclitaxel is used as a therapeutic clinical agent to treat breast cancer that exerts antitumor activity in numerous types of cancer cell. Curcumin (diferuloylmethane), a polyphenol derived from turmeric (Curcuma longa), possesses several properties that could enable it to exert an anticancer effect. Previous reports have demonstrated the synergistic effects of several chemotherapeutic drugs in combination with curcumin. Therefore, the aim of the current study was to evaluate cell death induced by curcumin and paclitaxel alone and in combination in human breast cancer cell lines: MCF7, an epithelial and luminal-like adenocarcinoma cell line triple positive for estrogen and progesterone receptor, and MDA-MB-234, a metastatic human breast cancer cell line triple negative for such receptors, as well as MCF-10F as a normal breast cell line. The results indicated that curcumin and paclitaxel induced apoptosis and necrosis, which was demonstrated through multiple methods, including assays of caspase-3/7 activity, Annexin V, poly(ADP-ribose) polymerase-1 activation and protein expression of caspase-3, nuclear factor (NF)-κB transcription factor and proliferating cell nuclear antigen. The results identified that the combination of curcumin and paclitaxel had a decreased effect on apoptosis in the malignant MDA-MB-231 cell line compared with in MCF7 or MCF-10F. It was demonstrated that the combined treatment with curcumin and paclitaxel resulted in a higher level of apoptosis compared with either substance alone in breast cancer cell lines. Therefore, breast cancer treatment may benefit from the use of a combination of drugs in chemotherapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Biomarkers, Tumor; Breast Neoplasms; Caspase 3; Caspase 7; Cell Proliferation; Curcumin; Drug Synergism; Female; Humans; NF-kappa B; Paclitaxel; Poly (ADP-Ribose) Polymerase-1; Tumor Cells, Cultured

Topics: Antineoplastic Agents, Phytogenic; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biotinylation; Breast Neoplasms; Chemistry, Pharmaceutical; Curcumin; Drug Carriers; Drug Delivery Systems; Drug Liberation; Drug Resistance, Neoplasm; Excipients; Glutathione; Humans; Inhibitory Concentration 50; MCF-7 Cells; Nanoparticles; Paclitaxel; Polyethylene Glycols; Solubility

Curcumin is a natural polyphenol with promising anticancer properties that undergoes pronounced metabolism in humans. In order to determine whether metabolism of curcumin also occurs in tumor cells and whether biotransformation has any impact on cytotoxicity, metabolism experiments were conducted with hormone-dependent ZR-75-1 and hormone-independent MDA-MB-231 human breast cancer cells. By using HPLC-ESI-Qq-TOF-MS, it was possible to identify one main metabolite, namely curcumin sulfate, in both cell lines. Its concentration in the cytoplasm and culture medium was 1.6- to 1.7-fold higher in ZR-75-1 cells than in MDA-MB-231 cells, concomitant with a 2-fold higher IC

Topics: Biotransformation; Breast Neoplasms; Cell Line, Tumor; Chromatography, Liquid; Curcumin; Estrogens; Female; Gas Chromatography-Mass Spectrometry; Humans; Time Factors

Emerging evidence suggests that curcumin can overcome drug resistance to classical chemotherapies, but poor bioavailability and low absorption have limited its clinical use and the mechanisms remain unclear. Also, Adriamycin (Adr) is one of the most active cytotoxic agents in breast cancer; however, the high resistant rate of Adr leads to a poor prognosis.. We utilized encapsulation in liposomes as a strategy to improve the bioavailability of curcumin and demonstrated that liposomal curcumin altered chemosensitivity of Adr-resistant MCF-7 human breast cancer (MCF-7/Adr) by MTT assay. The miRNA and mRNA expression profiles of MCF-7/S, MCF-7/Adr and curcumin-treated MCF-7/Adr cells were analyzed by microarray and further confirmed by real-time PCR. We focused on differentially expressed miR-29b-1-5p to explore the involvement of miR-29b-1-5p in the resistance of Adr. Candidate genes of dysregulated miRNAs were identified by prediction algorithms based on gene expression profiles. Networks of KEGG pathways were organized by the selected dysregulated miRNAs. Moreover, protein-protein interaction (PPI) was utilized to map protein interaction networks of curcumin regulated proteins.. We first demonstrated liposomal curcumin could rescue part of Adriamycin resistance in breast cancer and further identified 67 differentially expressed microRNAs among MCF-7/S, MCF-7/Adr and curcumin-treated MCF-7/Adr. The results showed that lower expressed miR-29b-1-5p decreased the IC50 of MCF-7/Adr cells and higher expressed miR-29b-1-5p, weaken the effects of liposomal curcumin to Adr-resistance. Besides, we found that 20 target genes (mRNAs) of each dysregulated miRNA were not only predicted by prediction algorithms, but also differentially expressed in the microarray. The results showed that MAPK, mTOR, PI3K-Akt, AMPK, TNF, Ras signaling pathways and several target genes such as PPARG, RRM2, SRSF1and EPAS1, may associate with drug resistance of breast cancer cells to Adr.. We determined that an altered miRNA expression pattern is involved in acquiring resistance to Adr, and that liposomal curcumin could change the resistance to Adr through miRNA signaling pathways in breast cancer MCF-7 cells.

Topics: Antibiotics, Antineoplastic; Breast Neoplasms; Curcumin; Doxorubicin; Drug Interactions; Drug Resistance, Neoplasm; Gene Regulatory Networks; Humans; Liposomes; MCF-7 Cells; MicroRNAs; Protein Interaction Maps; Signal Transduction

Recently, research has focused on targeting the oxidative and metabolic vulnerabilities in cancer cells. Natural compounds like curcumin that target such susceptibilities have failed further clinical advancements due to the poor stability and bioavailability as well as the need of high effective doses. We have synthesized and evaluated the anti-cancer activity of several monocarbonyl analogs of curcumin. Interestingly, two novel analogs (Compound A and I) in comparison to curcumin, have increased chemical stability and have greater anti-cancer activity in a variety of human cancer cells, including triple-negative, inflammatory breast cancer cells. In particular, the generation of reactive oxygen species was selective to cancer cells and occurred upstream of mitochondrial collapse and execution of apoptosis. Furthermore, Compound A in combination with another cancer-selective/pro-oxidant, piperlongumine, caused an enhanced anti-cancer effect. Most importantly, Compound A was well tolerated by mice and was effective in inhibiting the growth of human triple-negative breast cancer and leukemia xenografts in vivo when administered intraperitoneally. Thus, exploiting oxidative vulnerabilities in cancer cells could be a selective and efficacious means to eradicate malignant cells as demonstrated by the curcumin analogs presented in this report with high therapeutic potential.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Survival; Curcumin; Disease Models, Animal; Humans; Leukemia; Mice; Neoplasm Transplantation; Reactive Oxygen Species; Treatment Outcome

Purpose of this article is developing novel, inexpensive curcumin loaded chitosan nanoparticles with targeting ability. Curcumin loaded folate-modified-chitosan-nanoparticles (NPs) have been synthesized and fabricated via self-assembling process. Chemical structures of modified chains, nanoparticle size in dry and wet state, zeta potential, morphology of NPs, physical state of curcumin in NPs, drug release profile and cytotoxicity of NPs were investigated by FTIR, FE-SEM, DLS and XRD, UV-vis spectrophotometer, and MTT assay against L929 and MCF7 cell lines, respectively. Results show nanoparticle size in dry state varied in range of 119-127nm and curcumin was loaded into nanoparticles with 96.47% efficacy. Drug release studies showed by decreasing pH of release medium from 7.4 to 5, release rate of curcumin from NPs increased, which shows pH responsive capacity of folate-modified chitosan nanoparticles. Cell viability studies confirmed that curcumin loaded NPs have good potential as a drug delivery system for breast cancer therapy.

Topics: Breast Neoplasms; Chitosan; Curcumin; Drug Carriers; Drug Delivery Systems; Folic Acid; Humans; Hydrogen-Ion Concentration; Nanoparticles; Particle Size

Despite advantageous antitumor properties of doxorubicin, the considerable cytotoxicity of this chemotherapeutic agent has made it necessary to develop combination treatment strategies. The aim of the current study was to investigate the possible synergism between dendrosomal nanocurcumin (DNC) and doxorubicin in eliciting anticancer effects on MDA-MB-231 metastatic breast cancer cells. The expression levels of CXCL12/CXCR4 axis and Hedgehog pathway genes were evaluated in patient-derived breast carcinoma tissues by qRT-PCR. MTT assay, Annexin V-FITC staining followed by flowcytomety and wound healing assay were used to measure the effects caused by DNC and doxorubicin, alone and in combination, on the viability, apoptosis induction, and migration of MDA-MB-231 cells, respectively. Also, qRT-PCR was exploited to analyze the expression of Smo, NF-κB and CXCR4 in cancer cells. Our results revealed that combination treatment with DNC and doxorubicin leads to significantly decreased viability, increased apoptosis, and reduced migration of breast cancer cells compared with using each drug alone. Also, combination treatment is more efficient that single treatment in reducing the expression levels of NF-κB and Smo transcripts. Our findings provide convincing support for the notion that DNC could synergistically enhance the anticancer effects of doxorubicin on metastatic breast cancer cells by improving its anti-proliferative, pro-apoptotic, and anti-migratory activities. This may be mediated, in part, by downregulating CXCR4, NF-κB, and Smo genes. Overall, the findings of the current study suggest that DNC might be used as a synergistic agent for enhancing therapeutic efficiency and reducing toxic effects of doxorubicin on breast cancer cells.

Topics: Adult; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Chemokine CXCL12; Curcumin; Doxorubicin; Drug Synergism; Drug Therapy, Combination; Female; Gene Expression Regulation, Neoplastic; Hedgehog Proteins; Humans; Middle Aged; NF-kappa B; Receptors, CXCR4; Signal Transduction; Smoothened Receptor

Several studies have demonstrated that cancer stem cells (CSCs) are responsible for replenishing bulk tumor cells, generating new tumors and causing metastasis and relapse. Although combination therapy with multiple chemotherapeutics is considered to be a promising approach for simultaneously eliminating non-CSCs and CSCs, it is difficult to deliver drugs into the inner region of a solid tumor where the CSCs are located due to a lack of capillaries. Here, we synthesized a pH-sensitive polymer, poly(ethylene glycol)-benzoic imine-poly(γ-benzyl-l-aspartate)-b-poly(1-vinylimidazole) block copolymer (PPBV), to develop a pH multistage responsive micellar system for co-delivering paclitaxel and curcumin and synergistically eliminating breast cancer stem cells (bCSCs) and non-bCSCs. This pH multistage responsive micellar system could intelligently switch its surface charge from neutral to positive, de-shield its PEG layer and reduce its size after long-circulation and extravasation from leaky blood vessels at tumor sites, thus facilitating their cellular uptake and deep tumor penetration. These advantages were also beneficial for the combinational therapy efficacy of PTX and CUR to reach the maximum level and achieve superior tumor inhibition activity and effective bCSCs-killing capacity in vivo. Consequently, this pH multistage responsive micellar system is a powerful platform for collaborative therapy with PTX and CUR to simultaneously eliminate bCSCs and non-CSCs.

Topics: Animals; Antineoplastic Agents; Aspartic Acid; Breast Neoplasms; Cell Line, Tumor; Cell Survival; Curcumin; Drug Carriers; Drug Liberation; Drug Synergism; Female; Humans; Hydrogen-Ion Concentration; Imidazoles; Mice, Inbred BALB C; Micelles; Nanoparticles; Neoplastic Stem Cells; Paclitaxel; Particle Size; Polyethylene Glycols; Polyvinyls; Surface Properties

The X-linked inhibitor of apoptosis (XIAP) confers the resistance of various types of cancer to standard chemotherapeutic agents such as anthracycline and taxane. In breast cancer, XIAP is known to be overexpressed. However, the mechanisms underlying the overexpression of XIAP remain currently unclear. In order to elucidate the mechanisms responsible for the overexpression of the XIAP protein in breast cancer, we attempted to clarify the mechanisms by which the natural compound curcumin downregulates XIAP in breast cancer cells. In that process, we identified the ribosomal protein S3 (RPS3) as a curcumin‑binding protein using curcumin-fixed magnetic FG beads. The knockdown of RPS3 inhibited cell growth and induced apoptosis as well as the downregulation of XIAP in breast cancer cells. Although RPS3 is known to directly bind to and activate the nuclear factor-κB (NF-κB), which induces several anti-apoptotic genes such as XIAP, the knockdown of RPS3 unexpectedly reduced the levels of the XIAP protein, but not the mRNA level of XIAP and the transcription factor NF-κB activity. These results reveal that RPS3 upregulates XIAP independently of the NF-κB pathway in human breast cancer cells.

Topics: Apoptosis; Breast Neoplasms; Carrier Proteins; Cell Line, Tumor; Cell Proliferation; Curcumin; Female; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; NF-kappa B; Ribosomal Proteins; X-Linked Inhibitor of Apoptosis Protein

Poor bioavailability and non-specificity of chemotherapeutic agents are major challenges in breast cancer treatment. Antibodies and small molecules that block cell signaling pathways have shown promise in the clinic, but their application is also limited by the high costs and treatment dosages required. Novel therapies that aim to rapidly and specifically target malignant cells with long-lasting impact in the tumor microenvironment may ultimately improve clinical outcome in cancer patients. Here, we demonstrate that epidermal growth factor receptor (EGFR)-targeting GE11 peptides conjugated with PEGylated polylactic-co-glycolic acid (PLGA) nanoparticles can be used to effectively deliver an anti-cancer agent, curcumin, into EGFR-expressing MCF-7 cells in vitro and in vivo. Treatment of breast cancer cells and tumor-bearing mice with these curcumin-loaded nanoparticles gave rise to reduced phosphoinositide 3-kinase signaling, decreased cancer cell viability, attenuated drug clearance from the circulation, and suppressed tumor burden compared with free curcumin or non-EGFR targeting nanoparticles. The targeted nanoscale drug delivery system we describe here may provide a new strategy for the design of targeted cancer therapy vectors. Our study provides evidence that the efficacy of pharmacologic anti-cancer agents can be enhanced through their delivery in the form of modified nanoparticles that effectively target specific malignant cell types.

Topics: Animals; Breast Neoplasms; Curcumin; Drug Carriers; ErbB Receptors; Female; Humans; MCF-7 Cells; Mice; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Phosphatidylinositol 3-Kinases; Polylactic Acid-Polyglycolic Acid Copolymer; Xenograft Model Antitumor Assays

In vitro evaluation of toxicity and/or efficacy of nanostructured drug delivery systems involves the uses of different controls, including positive and negative controls, as well as a solution or dispersion of the drug in water. One of the most frequently solvent used to dilute poorly water soluble drugs to in vitro tests are dimethylsulfoxide (DMSO). However, its different specific surface area and different diffusion coefficients could make the comparative effects difficult. We proposed that a solvent-free dispersions having similar specific surface area could be a better control than drug in solution against cell lines.. We evaluate the effect of curcumin-loaded lipid-core nanocapsules, curcumin-loaded nanoemulsion and curcumin DMSO-water solution on viability and colony forming efficiency of human breast cancer cell line, MCF7.. The cytotoxic effect of nanocapsules at 24-72h was similar to nanoemulsion and lower than drug solution. However, the nanocapsules had a superior anticancer activity when long periods (10days) were evaluated, which highlight the sustained drug release by nanocapsules.. Our results showed a superior anticancer activity of curcumin-loaded lipid-core nanocapsules compared to curcumin-loaded nanoemulsion and curcumin dissolved in DMSO in long exposition time assay, wihch is not observed in short exposition time assays like MTT. When a poorly water-soluble drug is under investigation, the nanoemulsion prepared with the same compounds of the nanocapsules, except the polymer, could be a better control than DMSO-solution of drug.

Topics: Antineoplastic Agents; Breast Neoplasms; Curcumin; Delayed-Action Preparations; Dimethyl Sulfoxide; Drug Delivery Systems; Emulsions; Humans; Lipids; MCF-7 Cells; Nanocapsules; Particle Size; Polymers; Solubility; Solvents; Time Factors

Combination therapies are often explored to treat cancer. The use of curcumin as an adjuvant to current chemotherapies has been reported, whilst aminonaphthoquinones have shown potential as anticancer agents in various tumour cell lines. This study aimed at screening synthetic aminonathoquinone derivatives (Rau 008, Rau 010, Rau 015 and Rau 018) alone and in combination with curcumin for anti-breast cancer activity.. Combination effects were determined in MCF-7 breast cancer cells using combination index analyses. Synergistic anti-proliferative effects were further investigated in breast (MCF-7, MDA-MB-231), osteosarcoma (MG-63) and endometrial (HEC-1A) cancer-derived cells.. Rau 015 (15 μM) and curcumin (112.5 μM) significantly reduced MCF-7, MDA-MB-231 and MG-63 cell proliferation compared to individual treatment, indicating synergistic anti-proliferative effects. Rau 018 (30 μM) and curcumin (100 μM) displayed similar effects in MCF-7 and MG-63 cells.. We report on the potential of Rau 015 or Rau 018 as anti-breast cancer agents when combined with curcumin.

Topics: Alkaline Phosphatase; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Curcumin; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Drug Synergism; Female; Humans; Insulin-Like Growth Factor Binding Protein 3; MCF-7 Cells; Molecular Structure; Naphthoquinones; Receptors, Estrogen

The study aimed to investigate the effects of combination treatment of curcumin and β-interferon (IFN-β)/retinoic acid (RA) on breast cancer cells, including cell viability, apoptosis and migration, and to determine the mechanisms related to GRIM-19 through STAT3-dependent and STAT3-independent pathways.. The following groups were used for the in vitro experiment: control siRNA, GRIM-19 siRNA, IFN-β/RA and IFN-β/RA + curcumin. Cell viability is by the MTT method, cell apoptosis by flow cytometry and cell migration by wound healing experiment; GRIM-19, STAT3, survivin, Bcl-2, GADD153 and COX-2 expression was measured by Western blot. In vivo experiment, MCF-7 cells were subcutaneously injected into nude mice.. GRIM-19 siRNA promoted MCF-7 cell proliferation and migration; inhibited cell apoptosis; and promoted the expression of STAT3, survivin, Bcl-2 and MMP-9. IFN-β/RA inhibited cell proliferation and migration; promoted cell apoptosis; up-regulated GRIM-19; and inhibited the expression of STAT3, survivin, Bcl-2 and MMP-9. Combination treatment of curcumin and IFN-β/RA had a stronger effect than that of the IFN-β/RA group. In addition, curcumin and IFN-β/RA combination inhibited the expression of COX-2 and up-regulated GADD153.. Curcumin synergistically increases the effects of IFN-β/RA on breast cancer cells. The mechanism may be related to the up-regulation of GRIM-19 through STAT3-dependent and STAT3-independent pathways.

Topics: Animals; Apoptosis; Apoptosis Regulatory Proteins; Breast Neoplasms; Curcumin; Drug Synergism; Female; Humans; Interferon-beta; MCF-7 Cells; Mice; Mice, Nude; NADH, NADPH Oxidoreductases; Signal Transduction; STAT3 Transcription Factor; Tretinoin; Up-Regulation; Xenograft Model Antitumor Assays

Targeting tumor DNA damage and p53 pathway is a clinically established strategy in the development of cancer chemotherapeutics. Majority of anti-cancer drugs are delivered through parenteral route for reasons like severe toxicity, lack of stability, and poor enteral absorption. Current DNA targeting drugs in clinical like anthracycline suffers from major drawbacks like cardiotoxicity. Here, we report identification of a new orally active small molecule curcumin-triazole conjugate (CT-1) with significant anti-breast cancer activity in vitro and in vivo. CT-1 selectively and significantly inhibits viability of breast cancer cell lines; retards cells cycle progression at S phase and induce mitochondrial-mediated cell apoptosis. CT-1 selectively binds to minor groove of DNA and induces DNA damage leading to increase in p53 along with decrease in its ubiquitination. Inhibition of p53 with pharmacological inhibitor as well as siRNA revealed the necessity of p53 in CT-1-mediated anti-cancer effects in breast cancer cells. Studies using several other intact p53 and deficient p53 cancer cell lines further confirmed necessity of p53 in CT-1-mediated anti-cancer response. Pharmacological inhibition of pan-caspase showed CT-1 induces caspase-dependent cell death in breast cancer cells. Most interestingly, oral administration of CT-1 induces significant inhibition of tumor growth in LA-7 syngeneic orthotropic rat mammary tumor model. CT-1 treated mammary tumor shows enhancement in DNA damage, p53 upregulation, and apoptosis. Collectively, CT-1 exhibits potent anti-cancer effect both in vitro and in vivo and could serve as a safe orally active lead for anti-cancer drug development. © 2016 Wiley Periodicals, Inc.

Topics: Animals; Antineoplastic Agents; Apoptosis; Breast; Breast Neoplasms; Cell Line, Tumor; Curcumin; DNA; DNA Damage; Female; Humans; Molecular Docking Simulation; Rats; Triazoles; Tumor Suppressor Protein p53

The heterogeneity of breast cancer makes it a challenging solid tumor to diagnose and treat. A tumor suppressor Deleted in Liver Cancer 1 (DLC1) has been reported to be down-regulated or even silenced in several kinds of cancer including breast cancer. Curcumin has been reported to modulate the growth of tumor cells through regulation of multiple cell signaling pathways and modulate epigenetic changes by CpG demethylation of many tumor suppressor genes. This study was designed to investigate the effect of curcumin on the expression of Deleted in Liver Cancer 1 (DLC1) in human breast cancer cell line MDA-MB-361 and the underlying mechanism in vitro and in vivo. Curcumin induced DLC1 expression in a dose-dependent manner. In curcumin-treated cells, methylation of DLC1 promoter was reduced and active forms of RhoA and Cdc42 were also decreased. DLC1 expression was closely related to tumor cell growth, demonstrated by Ki67 staining. Curcumin inhibited DNA methyltransferase 1 expression through down-regulation of transcription factor Sp1. Consistent with the in vitro data, in vivo administration of curcumin inhibited the growth of implanted MDA-MB-361 cells and induced DLC1 expression in tumor tissue. In MDA-MB-361 cells, curcumin down-regulates the expression of Sp1 to inhibit the expression of DNA methyltransferase 1, thus subsequently reducing hypermethylation of DLC1 promoter to induce DLC1 expression.

Topics: Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Curcumin; DNA Methylation; DNA, Neoplasm; Female; Gene Expression Regulation, Neoplastic; GTPase-Activating Proteins; Humans; Promoter Regions, Genetic; Tumor Suppressor Proteins

Curcumin, a naturally occurring polyphenol, has been extensively studied for its broad-spectrum anticancer effects. The potential benefits are, however, limited due to its poor water solubility and rapid degradation which result in low bioavailability on administration.. This study encapsulates curcumin in nanoliposomes including an integrin-homing peptide combined with a C end R neuropilin-1 targeting motif for targeted delivery and receptor-mediated internalization, respectively.. The linear GHHNGR (Glycine-Histidine-Histidine-Asparagine-Glycine-Arginine) was synthesized through F-moc chemistry on 2-chlorotrityl chloride resin and conjugated to oleic acid. The lipoyl-peptide units were then co-assembled with lecithin and 0-75 mole % Tween-80 into liposomes. Curcumin was passively entrapped using a film hydration technique and its degradation profile was examined within seven consecutive days. The cytotoxic effects of the curcumin-loaded liposomes were studied on MCF-7 and MDA-MB-468, during 24 h exposure in MTT assay.. The maximum curcumin entrapment (15.5% W/W) and minimum degradation (< 23%) were obtained in a pH switch loading method from 5.7 to 8, in nanoliposomes (< 50 nm) containing oleyl-peptide, lecithin and Tween-80 (1:1:0.75 mole ratio). The oleyl-peptide did not prove any haemolytic activity (< 1.5%) up to 10-fold of its experimental concentration. The curcumin-loaded liposomes displayed significant reduction in the viabilities of MCF-7 (IC. This study indicated potential advantages of the peptide-conjugated liposomes in drug transport to the cancer cells. This feature might be an outcome of probable interactions between the targeted nanoliposomes with the integrin and neuropilin-1 receptors.

Topics: Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cell Survival; Curcumin; Dose-Response Relationship, Drug; Drug Carriers; Drug Compounding; Drug Stability; Endocytosis; Female; Humans; Inhibitory Concentration 50; Integrins; Liposomes; MCF-7 Cells; Nanoparticles; Neuropilin-1; Oleic Acid; Oligopeptides; Time Factors

Pharmaceutical industries spend more money in developing new and efficient methods for delivering successful drugs for anticancer therapy. Electrospun nanofibers and nanoparticles loaded with drugs have versatile biomedical applications ranging from wound healing to anticancer therapy. We aimed to attempt for fabricating elastomeric poly (l-lactic acid-co-ε-caprolactone) (PLACL) with Aloe Vera (AV), magnesium oxide (MgO) nanoparticles, curcumin (CUR) and β-cyclodextrin (β-CD) composite nanofibers to control the growth of MCF-7 cells for breast cancer therapy. The study focused on the interaction of MgO nanoparticle with CUR and β-CD inhibiting the proliferation of Michigan Cancer Foundation-7 (MCF-7) breast cancer cells. FESEM micrographs of fabricated electrospun PLACL, PLACL/AV, PLACL/AV/MgO, PLACL/AV/MgO/CUR and PLACL/AV/MgO/β-CD nanofibrous scaffolds achieved bead free, random and uniform nanofibers with fiber diameter in the range of 786±286, 507±171, 334±95, 360±94 and 326±80nm respectively. Proliferation of MCF-7 cells was decreased by 65.92% in PLACL/AV/MgO/CUR with respect to PLACL/AV/MgO nanofibrous scaffolds on day 9. The obtained results proved that 1% CUR interacting with MgO nanoparticles showed higher inhibition of MCF-7 cells among all other nanofibrous scaffolds thus serving as a promising biocomposite material system for the breast cancer therapy.

Topics: Antineoplastic Agents, Phytogenic; beta-Cyclodextrins; Breast Neoplasms; Cell Proliferation; Curcumin; Female; Humans; Manganese Compounds; MCF-7 Cells; Nanofibers; Nanoparticles; Oxides; Polyesters

The natural product curcumin and the chemotherapeutic agent doxorubicin have been used in the treatment of many cancers, including breast cancer. However, fast clearance and unspecific distribution in the body after intravenous injection are still challenges to be overcome by an ideal nano-sized drug delivery system in cancer treatment. In this study we design transferrin (Tf) decorated nanoparticles (NPs) to co-deliver CUR and DOX for breast cancer treatment. A pH-sensitive prodrug, transferrin-poly(ethylene glycol)-curcumin (Tf-PEG-CUR), was synthesized and used for the self‑assembling of NPs (Tf-PEG-CUR NPs). DOX is incorporated into the Tf-PEG-CUR NPs to obtain Tf-PEG-CUR/DOX NPs. In vitro cytotoxicity studies and in vivo antitumor activity were carried out using MCF-7 cells and mice bearing MCF-7 cells, respectively. Tf-PEG-CUR/DOX NPs has a particle size of 89 nm and a zeta potential of -15.6 mV. This system displayed remarkably higher efficiency than other systems both in vitro and in vivo. DOX and CUR were successfully loaded into nanocarriers. The in vitro cell viability assays revealed the combination of Tf-PEG-CUR and DOX NPs exhibited higher cytotoxicity in vitro in MCF-7 cells compared with Tf-PEG-CUR NPs alone. Using the breast cancer xenograft mouse model, we demonstrate that this co-encapsulation approach resulted in an efficient tumor-targeted drug delivery, decreased cytotoxic effects and exhibited stronger antitumor effect.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Curcumin; Doxorubicin; Drug Delivery Systems; Female; Humans; MCF-7 Cells; Mice, Inbred BALB C; Nanoparticles; Polyethylene Glycols; Prodrugs; Tissue Distribution; Transferrin; Xenograft Model Antitumor Assays

Increased mortality associated with breast cancer in women has spurred the studies to develop new drugs. Arabinogalactan (AG) and curcumin (Cur) are two natural products broadly explored in cancer therapy. Our major goal in the current study was to assess anticancer properties of combination these reagents in vitro on human breast cancer cells and in vivo utilizing animal model of breast cancer.. We evaluated cell proliferation, apoptosis, cell cycle, and protein expression in vitro on MDA-MB-231 human breast cancer cells. For in vivo studies, murine breast cancer cells were implanted into BALB/c mice. Thereafter, volume of the developing tumor was calculated and expression of Ki67 and p53 proteins was evaluated to analyze cell proliferation and apoptosis.. Combination of AG and Cur significantly decreased cell growth in human breast cancer cells without any significant effect on normal cell growth. This combination could increase cell population in sub-G1 phase, which was indicative of apoptosis. Western blotting showed that the combination of AG and Cur significantly increased Bax/Bcl2 ratio as well as cleaved-caspase3 level in MDA-MB-231 cells. Combination of AG and Cur promoted apoptosis by increasing ROS level, changing mitochondrial membrane and reduction of glutathione. In addition, in vivo studies in mouse showed that this combination could inhibit the progression of breast tumors through over-expression of p53 and reduction of Ki67 levels.. Our findings suggest that the combination of AG and Cur is of great potential to induce apoptosis in breast cancer cells in vitro and in vivo.

Topics: Animals; Apoptosis; Apoptosis Regulatory Proteins; Breast Neoplasms; Cell Line, Tumor; Cell Nucleus; Cell Proliferation; Curcumin; Female; G1 Phase; Galactans; Glutathione; Human Umbilical Vein Endothelial Cells; Humans; Intracellular Space; Membrane Potential, Mitochondrial; Mice, Inbred BALB C; Nitric Oxide; Organ Size; Reactive Oxygen Species; Staining and Labeling; Tumor Suppressor Protein p53; Weight Gain

Polymeric micelles have been widely explored preclinically as suitable delivery systems for poorly soluble chemotherapeutic drugs in cancer therapy. The present study reported the development of cholesterol (Ch)-conjugated poly(D,L-Lactide) (PLA)-based polymeric micelles (mPEG-PLA-Ch) for effective encapsulation and delivery of curcumin (CUR) at the tumor site. Cholesterol conjugation dramatically affected the particle size and improved drug loading (DL) and encapsulation efficiency (EE). mPEG-PLA-Ch-CUR showed bigger hydrodynamic diameter (104.6 ± 2.1 nm, and 169.3 ± 1.52 nm for mPEG-PLA and mPEG-PLA-Ch, respectively) due to increased size of the hydrophobic core. The newly developed polymer exhibited low critical micelles concentration (CMC) (25 μg/mL) which is close to lipid-based polymer, PEG-phosphatidyl ethanolamine (12.5 μg/mL) compared to mPEG-PLA (50 μg/mL). mPEG-PLA-Ch micelles exhibited relatively higher EE (93.74 ± 1.6%) and DL (11.86 ± 0.8%) compared to mPEG-PLA micelles (EE 91.89 ± 1.2% and DL 11.06 ± 0.8%). mPEG-PLA-Ch micelles were internalized by the cancer cells effectively and exhibited higher cytotoxicity compared to free CUR in both, murine melanoma (B16F10) and human breast cancer (MDA-MB-231) cells. mPEG-PLA-Ch exhibited satisfactory hemocompatibility indicating their potential for systemic application. Further, mPEG-PLA-Ch-CUR demonstrated higher rate of reduction of tumor volume in B16F10-xenografted tumor-bearing mice compared to free CUR. At the end of 22 days, the tumor reduced to 1.87-fold (627.72 ± 0.9 mm

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cholesterol; Curcumin; Drug Carriers; Female; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Micelles; Particle Size; Polyesters; Polyethylene Glycols; Polymers

One of the mechanisms for epigenetic silencing of tumor suppressor genes is hypermethylation of cytosine residue at CpG islands at their promoter region that contributes to malignant progression of tumor. Therefore, activation of tumor suppressor genes that have been silenced by promoter methylation is considered to be very attractive molecular target for cancer therapy. Epigenetic silencing of glutathione S-transferase pi 1, a tumor suppressor gene, is involved in various types of cancers including breast cancer. Epigenetic silencing of tumor suppressor genes can be reversed by several molecules including natural compounds such as polyphenols that can act as a hypomethylating agent. Curcumin has been found to specifically target various tumor suppressor genes and alter their expression. To check the effect of curcumin on the methylation pattern of glutathione S-transferase pi 1 gene in MCF-7 breast cancer cell line in dose-dependent manner. To check the reversal of methylation pattern of hypermethylated glutathione S-transferase pi 1, MCF-7 breast cancer cell line was treated with different concentrations of curcumin for different time periods. DNA and proteins of treated and untreated cell lines were isolated, and methylation status of the promoter region of glutathione S-transferase pi 1 was analyzed using methylation-specific polymerase chain reaction assay, and expression of this gene was analyzed by immunoblotting using specific antibodies against glutathione S-transferase pi 1. A very low and a nontoxic concentration (10 µM) of curcumin treatment was able to reverse the hypermethylation and led to reactivation of glutathione S-transferase pi 1 protein expression in MCF-7 cells after 72 h of treatment, although the IC

Topics: Breast Neoplasms; Cell Line, Tumor; Cell Survival; Curcumin; DNA Damage; DNA Methylation; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Glutathione S-Transferase pi; Humans; MCF-7 Cells

Albumin-based nanoparticles are widely used to delivery anticancer drug because they promote the accumulation of drugs in tumor sites. Nanoparticles with surface immobilized albumin are widely described in literature, although mixed nanoparticles with systematically modified ratios between albumin and PEG-based material are less common. In this work, hybrid nanoparticles were prepared by coassembly of a PEG-based amphiphilic block copolymer together with a polymer-protein conjugate. Poly(oligo(ethylene glycol) methyl ether acrylate)-poly(ε-caprolactone) (POEGMEA-PCL) was prepared by a combination of ring-opening polymerization and reversible addition-fragmentation chain transfer (RAFT) polymerization, while the polymer-protein conjugate was obtained by reacting poly(ε-caprolactone) with bovine serum albumin (BSA-PCL). Co-assembly of both amphiphiles at different ratios, with and without curcumin as a drug, led to hybrid nanoparticles with various amount of albumin on the particle surface. The resulting hybrid nanoparticles were similar in size (100-120 nm), but increasing the amount of albumin on the surface led to a more-negative ζ potential. The cytotoxicity of the curcumin-loaded nanoparticles was examined on several cell lines. The curcumin-loaded nanoparticles with high amount of albumin led to high cytotoxicity against breast cancer cell lines (MDA-MB-231 and MCF-7), which coincided with high cellular uptake. However, the cytotoxicity of the curcumin-loaded nanoparticles against CHO cells and RAW264.7 cells was reduced, suggesting that albumin can facilitate selectivity toward cancer cells.

Topics: Animals; Antineoplastic Agents; Breast; Breast Neoplasms; Cattle; Cell Line, Tumor; CHO Cells; Cricetulus; Curcumin; Drug Carriers; Female; Humans; Mice; Models, Molecular; Nanoparticles; Polyesters; Polyethylene Glycols; RAW 264.7 Cells; Serum Albumin, Bovine

The aim of current study was to use methylene blue-curcumin ion pair nanoparticles and single dyes as photosensitizer for comparison of photodynamic therapy (PDT) efficacy on MDA-MB-231 cancer cells, also various light sources effect on activation of photosensitizer (PS) was considered.. Ion pair nanoparticles were synthesized using opposite charge ions precipitation and lyophilized. The PDT experiments were designed and the effect of PSs and light sources (Red LED (630nm; power density: 30mWcm. The results show that the ion pairing of methylene blue and curcumin enhance the photodynamic activity of both dyes and the cytotoxicity of ion pair nanoparticles on the MDA-231 breast cancer cell line. Blue and red LED light sources were used for photo activation of photosensitizers. The results demonstrated that both dyes can activate using red light LED better than blue light LED for singlet oxygen producing.. Nano scale ion pair precipitating of methylene blue-curcumin enhanced the cell penetrating and subsequently cytotoxicity of both dyes together.

Topics: Apoptosis; Breast Neoplasms; Cell Line, Tumor; Curcumin; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Humans; Methylene Blue; Nanoparticles; Photochemotherapy; Photosensitizing Agents; Treatment Outcome

Diarylheptanoids from Curcuma comosa, of the Zingiberaceae family, exhibit diverse estrogenic activities. In this study we investigated the estrogenic activity of a major hydroxyl diarylheptanoid, 7-(3,4 -dihydroxyphenyl)-5-hydroxy-1-phenyl-(1E)-1-heptene (compound 092) isolated from C. comosa. The compound elicited different transcriptional activities of estrogen agonist at low concentrations (0.1-1 μM) and antagonist at high concentrations (10-50 μM) using luciferase reporter gene assay in HEK-293T cells. In human breast cancer (MCF-7) cells, compound 092 showed an anti-estrogenic activity by down-regulating ERα-signaling and suppressing estrogen-responsive genes, whereas it attenuated the uterotrophic effect of estrogen in immature ovariectomized rats. Of note, compound 092 promoted mouse pre-osteoblastic (MC3T3-E1) cell differentiation and the related bone markers, indicating its positive osteogenic effect. Our findings highlight a new, nonsteroidal, estrogen agonist/antagonist of catechol diarylheptanoid from C. comosa, which is scientific evidence supporting its potential as a dietary supplement to prevent bone loss with low risk of breast and uterine cancers in postmenopausal women.

Topics: 3T3 Cells; Animals; Breast Neoplasms; Cell Differentiation; Cell Proliferation; Curcuma; Diarylheptanoids; Estrogen Receptor alpha; Female; Humans; Mice; Osteoblasts; Phytoestrogens; Plant Extracts; Rats; Rats, Wistar; Selective Estrogen Receptor Modulators; Uterus

Breast cancer remains the second most common disease worldwide. Radiotherapy, alone or in combination with chemotherapy, is widely used after surgery as a treatment for cancer with proven therapeutic efficacy manifested by reduced incidence of loco-regional and distant recurrences. However, clinical evidence indicates that relapses occurring after radiotherapy are associated with increased metastatic potential and poor prognosis in the breast. Among the anticarcinogenic and antiproliferative agents, curcumin is a well-known major dietary natural yellow pigment derived from the rhizome of the herb Curcuma longa (Zingiberaceae). The aim of the present study was to analyze the differential expression of metastatic genes in radiation- and estrogen-induced breast cancer cell model and the effect of curcumin on such metastatic genes in breast carcinogenesis. Expression levels of TGF-α and TGFβ1 genes were upregulated in MCF-10F and downregulated in Tumor2 cell lines treated with curcumin. Expression levels of other genes such as caspase 9 and collagen 4 A2 were upregulated in both MCF-10F and Tumor2-treated cell lines. Integrin α5 and cathepsin B and D decreased its expression in Tumor2, whereas E-Cadherin, c-myc and CD44 expressions were only increased in MCF-10F. It can be concluded that metastatic genes can be affected by curcumin in cancer progression and such substance can be used in breast cancer patients with advanced disease without side-effects commonly observed with therapeutic drugs.

Topics: Antioxidants; Breast Neoplasms; Carcinogenesis; Cell Line, Tumor; Curcuma; Estrogens; Female; Gene Expression Regulation, Neoplastic; Humans; Neoplasm Metastasis; Neoplasm Proteins; Neoplasm Recurrence, Local; Prognosis; Transforming Growth Factor alpha; Transforming Growth Factor beta1

Furanodiene is one of the major bioactive components isolated from the natural product of the plant, Curcuma wenyujin Y.H. Chen et C. Ling. Furanodiene has been found to exert anticancer effects in various types of cancer cell lines, as well as exhibit antimetastatic activities. However, the antimetastatic capacity of furanodiene in combination with the common chemotherapy drug doxorubicin has not been investigated. We found that doxorubicin at a non-toxic concentration induced cell migration and cell invasion in highly metastatic breast cancer cells. Combinational treatments with furanodiene and doxorubicin blocked the invasion and migration of MDA-MB-231 breast cancer cells in vitro. We also clarified the effects of the combination on the signaling pathways involved in migration, invasion, and cytoskeletal organization. When combined with doxorubicin, furanodiene downregulated the expression of integrin αV and β-catenin and inhibited the phosphorylation of paxillin, Src, focal adhesion kinase (FAK), p85, and Akt. Moreover, combinational treatments also resulted in a decrease in matrix metalloproteinase-9 (MMP-9). Further study demonstrated that the co-treatments with furanodiene did not significantly alter the effects of doxorubicin on the tubulin cytoskeleton, represented by no influence on the expression levels of RhoA, Cdc42, N-WASP, and α/β tubulin. These observations indicate that furanodiene is a potential agent that may be utilized to improve the anticancer efficacy of doxorubicin and overcome the risk of chemotherapy in highly metastatic breast cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Curcuma; Doxorubicin; Female; Focal Adhesion Kinase 1; Furans; Gene Expression Regulation, Neoplastic; Heterocyclic Compounds, 2-Ring; Humans; Matrix Metalloproteinase 9; Neoplasm Invasiveness; Neoplasm Proteins; Plant Extracts; Signal Transduction

The anti-cancer property of curcumin, an active component of turmeric, is limited due to its poor solubility, stability and bioavailability. To enhance its efficacy, we designed a novel series of twenty-four monocarbonyl curcumin analogue-1,2,3-triazole conjugates and evaluated their anti-cancer activity towards endocrine related cancers. The new compounds (17-40) were synthesized through CuAAC click reaction and SAR analysis carried out. Out of these all, compound 17 showed most significant anti-cancer activity against prostate cancer cells with IC50 values of 8.8μM and 9.5μM in PC-3 and DU-145 cells, respectively. Another compound 26 showed significant anti-cancer activity against breast cancer cells with IC50 of 6μM, 10μM and 6.4μM in MCF-7, MDA-MB-231 and 4T1 cells, respectively while maintaining low toxicity towards non-cancer originated cell line, HEK-293. Compounds 17 and 26 arrested cell cycle and induced mitochondria-mediated apoptosis in cancer cells. Further, both of these compounds significantly down-regulated cell proliferation marker (PCNA), inhibited activation of cell survival protein (Akt phosphorylation), upregulated pro-apoptotic protein (Bax) and down-regulated anti-apoptotic protein (Bcl-2) in their respective cell lines. In addition, in vitro stability, solubility and plasma binding studies of the compounds 17 and 26 showed them to be metabolically stable. Thus, this study identified two new curcumin monocarbonyl-1,2,3-triazole conjugate compounds with more potent activity than curcumin against breast and prostate cancers.

Topics: Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; Breast Neoplasms; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Click Chemistry; Curcumin; Down-Regulation; Drug Screening Assays, Antitumor; Female; Half-Life; HEK293 Cells; Humans; Male; Membrane Potential, Mitochondrial; Proliferating Cell Nuclear Antigen; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Triazoles

A major challenge in pharmaceutical research is effective targeting strategies to their sites of action. Emerging knowledge and the current progress in nanotechnology based delivery systems has opened up exciting ways towards successful targeted nanodelivery systems. For cancer therapy, nanoparticle-based drug formulations hold several advantages over free drugs, including improved pharmacokinetics, enhanced tumor accumulation, reduced systemic exposure and side effects and better patient compliance. The goal of this study was to validate the in vivo targeting potential and evaluate the combinatorial therapeutic potential of novel Annexin A2 (AnxA2) antibody-conjugated curcumin loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (AnxA2-CPNP) against metastatic breast cancer. As a first step, we demonstrated that the cell-surface expression of AnxA2 is increases during breast cancer progression with very high expression in highly malignant cancer cells and basal expression in non-malignant cells. This confirmed AnxA2 as an excellent target for targeting our curcumin nanoparticles. Our results indicate that AnxA2-CPNP showed increased uptake in highly metastatic breast cancer cells than untargeted nanoparticles due to the differential AnxA2 expression. Cell viability, plasmin generation and wound healing assays reveal that AnxA2-CPNPs effectively inhibited cell proliferation, invasion and migration, key elements for cancer growth and metastasis. Further, angiogenesis assay illustrated that AnxA2-CPNPs decreased the formation of tube capillaries, thus inhibiting neoangiogenesis, a critical element in tumor growth. Live animal imaging demonstrated that AnxA2-PNPs and AnxA2-CPNPs effectively targeted and accumulated in the tumor as seen by the increased fluorescence intensity on the live scans. Xenograft studies in mice showed significant regression of breast tumor as a result of both effective targeting, accumulation and sustained release of curcumin in the tumor. In conclusion, AnxA2-CPNPs were successfully validated for their breast tumor targeting potential and its improved therapeutic efficacy against metastatic breast cancer.

Topics: Animals; Annexin A2; Antibodies, Monoclonal; Breast Neoplasms; Cell Line, Tumor; Curcumin; Female; Humans; Lactic Acid; Mice; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Theranostic Nanomedicine; Xenograft Model Antitumor Assays

Curcumin diethyl disuccinate (CDD) is a succinate prodrug of curcuminoids that has better stability in human plasma and improved in vitro cytotoxicity compared to curcumin. Therefore, CDD has the potential for further development as an anticancer agent. In this study, we focused on optimization of the formulation of CDD-loaded chitosan/alginate nanoparticles using Box-Behnken statistical design to enhance the therapeutic efficacy of CDD. Oil-in-water emulsification followed by ionotropic gelification was used to prepare the CDD-loaded chitosan/ alginate nanoparticles. A formulation with a 0.05:1 chitosan/alginate mass ratio, 0.65% (w/v) Pluronic F127 and 1.5 mg/ml CDD was found to be optimal. FTIR, TGA and XRD confirmed the encapsulation of CDD molecules in the nanoparticles. In vitro cytotoxicity and cellular uptake studies showed that CDD-loaded chitosan/alginate nanoparticles had significantly higher cytotoxicity and cellular uptake in human breast adenocarcinoma MDA-MB-231 cells, compared to free CDD. Physical and chemical stability studies indicated that the optimally formulated CDD-loaded chitosan/alginate nanoparticles were stable at 4 °C for 3 months.

Topics: Alginates; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cell Line, Tumor; Chitosan; Curcumin; Drug Compounding; Drug Stability; Emulsions; Excipients; Female; Humans; Nanoparticles; Poloxamer; Prodrugs; Succinates

Breast cancer generally shows poor prognosis because of its invasion and metastasis. Lysophosphatidic acid (LPA) induces and aggravates cancer invasion and metastasis by activating its downstream signal pathways. RhoA/ROCK/MMP signaling was found one of the LPA-induced pathways, which may be involved in invasion of breast cancer. Furthermore, we investigated whether this pathway was involved in curcumin's effect against LPA-induced invasion. LPA incubation was used to enhance invasion of MCF-7 breast cancer cells. RhoA expression was knocked-down by siRNA technique. MTT assay was used to evaluate the proliferation. Transwell assay was utilized to investigate the invasion ability of MCF-7 cells. Real-time PCR and Western blotting were used to assess the expressions of RhoA, ROCK1, ROCK2, MMP2 and MMP9 at both translational and transcriptional levels. The RhoA and ROCK activities were also evaluated. LPA incubation significantly boosted invasion rate of MCF-7. RhoA silencing by siRNA dramatically inhibited LPA-enhanced invasion. Concurrently, RhoA and ROCK activities and expression levels of RhoA, ROCK1, ROCK2, MMP2 and MMP9 were down-regulated by RhoA siRNA transfection. In order to avoid influence of cytotoxicity of curcumin, concentrations below 45 μmol/L were selected to further investigate the mechanism of curcumin's anti-invasion effect. Invasion of LPA-incubated MCF-7 cells was impaired by curcumin in a concentration-dependent manner. Concurrently, RhoA and ROCK activities and expression levels of RhoA, ROCK1, ROCK2, MMP2 and MMP9 were down-regulated by curcumin in a concentration-dependent manner. In conclusion, RhoA/ROCK/MMPs pathway activation is involved in LPA-induced invasion in MCF-7 cells; curcumin inhibited LPA-induced invasion in MCF-7 cells by attenuating RhoA/ROCK/MMPs pathway.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Movement; Cell Proliferation; Curcumin; Female; Gene Expression Regulation, Neoplastic; Humans; Lysophospholipids; Matrix Metalloproteinases; MCF-7 Cells; Neoplasm Invasiveness; rho-Associated Kinases; rhoA GTP-Binding Protein; Signal Transduction

Curcumin-based structural modification for developing more effective curcumin analogues has been drawning increasing attention. As alternative approach, using LC/MS guided purification, we previously obtained a series of novel natural terpene-conjugated curcuminoids from turmeric, and some of them exhibited even more potent anti-cancer activity against multiple types of cancer cells than curcumin. The purpose of this follow-up study was designed to decipher the mechanisms involved in anti-cancer activity of these novel curcumin analogues. Apoptosis was evaluated using sub-G1 analysis by flow cytometry and Cell Death ELISA Kit. Changes of protein expression were analyzed by western blotting. RNA interference was employed to inhibit expression of specific protein. We found that bisabolocurcumin ether (T1) and demethoxybisabolocurcumin ether (T2) were able to trigger much stronger apoptosis induction in multiple types of cancer cells than curcumin, which was attributed to persistent and stronger ROS generation. ROS induction by T1 resulted in activation of p38/H2AX axis and p53. Inhibition of p38/H2AX led to a significant reduction of apoptosis, whereas inactivation of p53 caused a dramatically enhanced H2AX phosphorylation and apoptosis induction, suggesting activation of p38/H2AX contributed to apoptosis induction by T1, whereas p53 activation protected novel curcumins-induced apoptosis via suppression of H2AX activation. Our findings provide mechanistic support for the potential use of terpene-conjugated curcuminoids as a novel class of cancer chemopreventive agents. © 2015 Wiley Periodicals, Inc.

Topics: Antineoplastic Agents; Apoptosis; Breast; Breast Neoplasms; Cell Line, Tumor; Curcumin; Female; Histones; Humans; Neoplasms; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Reactive Oxygen Species; Signal Transduction; Terpenes

Breast cancer is the most frequently occurring cancer among women throughout the world. Natural compounds such as curcumin hold promise to treat a variety of cancers including breast cancer. However, curcumin's therapeutic application is limited, due to its rapid degradation and poor aqueous solubility. On the other hand, previous studies have stated that drug delivery using nanoparticles might improve the therapeutic response to anticancer drugs. Poly(N-isopropylacrylamide-co-methacrylic acid) (PNIPAAm-MAA) is one of the hydrogel copolymers utilized in the drug delivery system for cancer therapy. The aim of this study was to examine the cytotoxic potential of curcumin encapsulated within the NIPAAm-MAA nanoparticle, on the MCF-7 breast cancer cell line. In this work, polymeric nanoparticles were synthesized through the free radical mechanism, and curcumin was encapsulated into NIPAAm-MAA nanoparticles. Then, the cytotoxic effect of curcumin-loaded NIPAAm-MAA on the MCF-7 breast cancer cell line was measured by MTT assays. The evaluation of the results showed that curcumin-loaded NIPAAm-MAA has more cytotoxic effect on the MCF-7 cell line and efficiently inhibited the growth of the breast cancer cell population, compared with free curcumin. In conclusion, this study indicates that curcumin-loaded NIPAAm-MAA suppresses the growth of the MCF-7 cell line. Overall, it is concluded that encapsulating curcumin into the NIPAAm-MAA copolymer could open up new avenues for breast cancer treatment.

Topics: Acrylamides; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Proliferation; Cell Survival; Curcumin; Drug Carriers; Drug Liberation; Humans; Kinetics; MCF-7 Cells; Nanoparticles; Polymethacrylic Acids

Delivery of anti-cancer drugs into the cancer cells or tissues by multifunctional nanocarriers may provide a new paradigm in cancer treatment. In this study, folate (FA) decorated nanostructured lipid carriers (NLCs) were constructed as nanomedicine for the delivery of curcumin (CUR).. CUR-loaded NLCs (CUR-NLCs) were prepared. FA containing polyethylene glycol (PEG)-distearoylphosphatidylethanolamine (DSPE) (FA-PEG-DSPE) was synthesized and used for the decoration of CUR-NLCs. Their particle size, zeta potential, and drug encapsulation efficiency (EE) were evaluated. In vitro cytotoxicity study FA decorated CUR-NLCs (FA-CUR-NLCs) was tested in MCF-7 human breast cancer cells (MCF-7 cells). In vivo anti-tumor efficacies of the carriers were evaluated on mice bearing breast cancer model.. The optimum FA-CUR-NLCs formulations with the particle size of 127 nm and with a +13 mV surface charge. The growth of MCF-7 cells in vitro was obviously inhibited. FA-CUR-NLCs also displayed the best anti-tumor activity than other formulations in vivo.. The results demonstrated that FA-CUR-NLCs were efficient in selective delivery to cancer cells over-expressing FA receptors (FRs). Also FA-CUR-NLCs transfer CUR to the breast cancer cells, enhance the anti-tumor capacity. Thus, FA-CUR-NLCs could prove to be a superior nanomedicine to achieve tumor therapeutic efficacy.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Chemistry, Pharmaceutical; Curcumin; Drug Carriers; Drug Delivery Systems; Female; Folic Acid; Humans; Lipids; MCF-7 Cells; Mice; Nanostructures; Phosphatidylethanolamines; Polyethylene Glycols

This work describes the synthesis of block co-polymeric micelles, methoxy-poly(ethylene glycol)-poly(D,L-lactide) (mPEG-PLA) to encapsulate Curcumin (CUR), thereby improving the dispersibility and chemical stability of curcumin, prolonging its cellular uptake and enhancing its bioavailability.. CUR-mPEG-PLA micelles, was prepared using the thin-film hydration method and evaluated in vitro. The preparation process was optimized with a central composite design (CCD). Micelles were characterized by size, transmission electron microscopy, loading capacity, and critical micelle concentration (CMC). The cytotoxicity of CUR-mPEG-PLA micelles was investigated against murine melanoma cells, B16F10 and human breast cancer cells, MDA-MB-231.. The average size of the CUR-mPEG-PLA micelles was 110 ± 5 nm with polydispersity index in the range of 0.15-0.31, and the encapsulating efficiency for CUR was 91.89 ± 1.2, and 11.06 ± 0.8% for drug-loading. Sustained release of CUR from micelles was observed with 9.73% CUR release from micelles compared to 64.24% release of free curcumin in first 6 h under sink condition. The CUR-mPEG-PLA was efficiently taken up by the cancer cells, B16F10 and MDA-MB-231. Following 24 h incubation, CUR-mPEG-PLA induced higher cytotoxicity compared to free CUR in MDA-MB-231 cell lines indicating exposure of higher dose of free CUR to cells lead to up-regulation of drug efflux mechanisms leading to decreased cell death in case of free CUR administration.. Our results indicate that the proposed micellar system has the potential to serve as an efficient carrier for CUR by effectively solubilizing, stabilizing and delivering the drug in a controlled manner to the cancer cells.

Topics: Animals; Antineoplastic Agents; Breast; Breast Neoplasms; Cell Death; Cell Line, Tumor; Curcumin; Drug Carriers; Female; Humans; Melanoma; Mice; Micelles; Polyesters; Polyethylene Glycols

There is a need for new, safe and efficacious drug therapies for the treatment of estrogen receptor (ER)-negative breast cancers. Raloxifene and the 2nd generation curcumin derivative 2,6-bis(pyridin-4-ylmethylene)-cyclohexanone (RL91) have been shown to inhibit the growth of ER-negative breast cancer cells in vitro and in vivo. We investigated whether RL91 could enhance the growth-suppressive effects mediated by raloxifene in MDA-MB-231, MDA-MB-468, Hs578t and SkBr3 human breast cancer cell lines. The cytotoxicity was consistent across the cell lines but RL91 was more potent. EC50 values for RL91 were 1.2-2 µM while EC50 values for raloxifene were 9.6-11.2 µM. When the cells were treated with raloxifene (15 µM), RL91 (1 µM) or a combination of the two for 6-72 h, the combination treatment consistently elicited significantly greater cytotoxicity compared to all other treatments. In SkBr3 cells the combination treatment caused significantly more cells to undergo G1 arrest compared to raloxifene. In all cell lines apoptosis was synergistically induced by the combination treatment, as shown by both flow cytometery and cleaved caspase-3. Furthermore, the stress kinase p38 was increased and EFGR isoforms were decreased by both raloxifene and raloxifene + RL91. The anti-angiogenic anti-metastatic potential of raloxifene was not increased by RL91, as MDA-MB-231 cell migration and invasion as well as endothelial tube formation by HUVEC cells was not different between raloxifene (10 µM) and the combination of raloxifene + RL91. Thus, our findings provide evidence that RL91 increases the ability of raloxifene to suppress ER-negative cancer cell growth by increasing the number of apoptotic cells. The broad effect of this drug combination across a range of ER-negative breast cancer cell lines indicates that this drug combination should be explored further in order to find a safe and efficacious therapy for ER-negative breast cancer.

Topics: Apoptosis; Breast Neoplasms; Caspase 3; Cell Line, Tumor; Cell Movement; Curcumin; Drug Synergism; Female; Human Umbilical Vein Endothelial Cells; Humans; Neoplasm Invasiveness; Raloxifene Hydrochloride; Receptors, Estrogen; Signal Transduction

Synthesis of metal nanoparticles for improving therapeutic index and drug delivery is coming up as an attractive strategy in the mainstream of cancer therapeutic research. In the present study, curcumin-capped copper nanoparticles (CU-NPs) were evaluated as possible inhibitors of in vivo angiogenesis, pro-angiogenic cytokines involved in promoting tumor angiogenesis along with inhibition of cell proliferation and migration of breast cancer cell line MDA-MB-231. The antiangiogenic potential was assessed using in vivo chorioallantoic membrane (CAM) model. 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT)-based cytotoxicity assay was used to assess the effect of CU-NPs against proliferation of breast cancer cell line. The wound healing migration assay was used to evaluate the effects of CU-NPs on the migration ability of breast cancer cell line. Native curcumin (CU) was used as a reference compound for comparison purpose. The result of the present investigation indicates that CU-NPs could not demonstrate impressive antiangiogenic or anticancer activities significantly as compared to native CU. The possible mechanisms of experimental outcomes are discussed in the light of the methods of nanoparticle synthesis in concert with the current state of the art literature.

Topics: Angiogenesis Inhibitors; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Copper; Curcumin; Drug Carriers; Drug Delivery Systems; Female; Humans; Nanoparticles; Neovascularization, Pathologic

Previous studies have evidenced that the anticancer potential of curcumin (diferuloylmethane), a main yellow bioactive compound from plant turmeric was mediated by interfering with PI3K/Akt signaling. However, the underlying molecular mechanism is still poorly understood. This study experimentally revealed that curcumin treatment reduced Akt protein expression in a dose- and time-dependent manner in MDA-MB-231 breast cancer cells, along with an activation of autophagy and suppression of ubiquitin-proteasome system (UPS) function. The curcumin-reduced Akt expression, cell proliferation, and migration were prevented by genetic and pharmacological inhibition of autophagy but not by UPS inhibition. Additionally, inactivation of AMPK by its specific inhibitor compound C or by target shRNA-mediated silencing attenuated curcumin-activated autophagy. Thus, these results indicate that curcumin-stimulated AMPK activity induces activation of the autophagy-lysosomal protein degradation pathway leading to Akt degradation and the subsequent suppression of proliferation and migration in breast cancer cell.

Topics: Antineoplastic Agents; Autophagy; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Curcumin; Female; Gene Expression Regulation, Neoplastic; Humans; Proto-Oncogene Proteins c-akt

Bcl-2 protein has been contributed with number of genes which are involved in oncogenesis. Among the many targets of Bcl-2, NFκB have potential role in induction of cell cycle arrest. Curcumin has potential therapeutic effects against breast cancer through multiple signaling pathways. In this study, we investigated the role of curcumin in induction of cell cycle arrest via regulating of NFκB and polyamine biosynthesis in wt and Bcl-2+ MCF-7 cells. To examine the effect of curcumin on cell cycle regulatory proteins, PI3K/Akt, NFκB pathways and polyamine catabolism, we performed immunoblotting assay. In addition, cell cycle analysis was performed by flow cytometry. The results indicated that curcumin induced cell cycle arrest at G2/M phase by downregulation of cyclin B1 and Cdc2 and inhibited colony formation in MCF-7wt cells. However, Bcl-2 overexpression prevented the inhibition of cell cycle associated proteins after curcumin treatment. The combination of LY294002, PI3K inhibitor, and curcumin induced cell cycle arrest by decreasing CDK4, CDK2 and cyclin E2 in Bcl-2+ MCF-7 cells. Moreover, LY294002 further inhibited the phosphorylation of Akt in Bcl-2+ MCF-7 cells. Curcumin could suppress the nuclear transport of NFκB through decreasing the interaction of P-IκB-NFκB. The combination of wedelolactone, NFκB inhibitor, and curcumin acted different on SSAT expression in wt MCF-7 and Bcl-2+ MCF-7 cells. NFκB inhibition increased the SSAT after curcumin treatment in Bcl-2 overexpressed MCF-7 cells. Inhibition of NFκB activity as well as suppression of ROS generation with NAC resulted in the partial relief of cells from G2/M checkpoint after curcumin treatment in wt MCF-7 cells. In conclusion, the potential role of curcumin in induction of cell cycle arrest is related with NFκB-regulated polyamine biosynthesis.

Topics: Acetyltransferases; Apoptosis; Breast Neoplasms; Cell Cycle Checkpoints; Cell Proliferation; Cell Survival; Chromones; Coumarins; Curcumin; G2 Phase Cell Cycle Checkpoints; Genes, bcl-2; Humans; MCF-7 Cells; Morpholines; NF-kappa B; Phosphatidylinositol 3-Kinases; Polyamines; Signal Transduction

Small-molecule chemosensitizers can reverse cancer multidrug resistance (MDR), thus significantly improving the in vitro effect of chemotherapy drugs for MDR cancer cells, however, their in vivo effects are not always very good, because they are difficult to effectively accumulate in tumor and enter the same cancer with chemotherapy drugs after systemic administration due to individual biopharmaceutical properties. To overcome these limitations, here we study a novel nanoparticular pre-chemosensitizer which can be also used as nanocarrier of chemotherapy drugs. We take an 'all in one' approach to develop a self-assembled nanoparticle formula of amphiphilic poly(curcumin-dithiodipropionic acid)-b-poly(ethylene glycol)-biotin. The nanoparticle is capable of tumor-targeted delivery, responsive degradation at the intracellular level of glutathione and subsequent intracellular co-release of the chemosensitizer curcumin and the encapsulated chemotherapeutic drug doxorubicin to maximize a synergistic effect of chemosensitization and chemotherapy. We demonstrate that the antitumor efficacy of nanoparticle is much superior to that of doxorubicin in the multidrug resistant MCF-7/ADR xenografted nude mice.

Topics: Animals; Breast Neoplasms; Curcumin; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Glutathione; Humans; MCF-7 Cells; Mice; Nanoparticles; Polyethylene Glycols; Xenograft Model Antitumor Assays

The purpose of this study was to develop folic acid functionalized long-circulating co-encapsulated docetaxel (DTX) and curcumin (CRM) solid lipid nanoparticles (F-DC-SLN) to improve the pharmacokinetic and efficacy of DTX therapy. F-DC-SLN was prepared by hot melt-emulsification method and optimized by face centered-central composite design (FC-CCD). The SLN was characterized in terms of size and size distribution, drug entrapment efficiency and release profile. The cytotoxicity and cell uptake of the SLN formulations were evaluated in MCF-7 and MDA-MB-231 cell lines. The in vivo pharmacokinetic and biodistribution were studied in Wistar rats. F-DC-SLN exhibited 247.5 ± 3.40 nm particle size with 73.88 ± 1.08% entrapment efficiency and zeta potential of 14.53 ± 3.6 mV. Transmission electron microscopy (TEM) revealed spherical morphology of the SLN. Fluorescence microscopy confirmed the targeting efficacy of F-DC-SLN in MCF-7 cells. F-DC-SLN exhibited a significant increase in area under the curve (594.21 ± 64.34 versus 39.05 ± 7.41 μg/mL h) and mean residence time (31.14 ± 19.94 versus 7.24 ± 4.51 h) in comparison to Taxotere®. In addition, decreased DTX accumulation from F-DC-SLN in the heart and kidney in comparison to Taxotere may avoid to toxicity these vital organs. In conclusion, the F-DC-SLN improved the efficacy and pharmacokinetic profile of DTX exhibiting enhanced potential in optimizing breast cancer therapy.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Chemistry, Pharmaceutical; Curcumin; Docetaxel; Drug Carriers; Drug Liberation; Female; Folic Acid; Humans; Lipids; MCF-7 Cells; Nanoparticles; Rats; Rats, Wistar; Taxoids; Tissue Distribution

High levels of fatty acid synthase (FAS) expression have been found in many tumors, including prostate, breast, and ovarian cancers, and inhibition of FAS has been reported to obstruct tumor growth in vitro and in vivo. Curcumin is one of the major active ingredients of Curcuma longa, which has been proven to inhibit the growth of cancer cells. In the present study, we investigated the potential activity of curcumin as a FAS inhibitor for chemoprevention of breast cancer. As a result, curcumin induced human breast cancer MDA-MB-231 cell apoptosis with the half-inhibitory concentration value of 3.63 ± 0.26 µg/ml, and blocked FAS activity, expression and mRNA level in a dose-dependent manner. Curcumin also regulated B-cell lymphoma 2 (Bcl-2), Bax and p-Akt protein expression in MDA-MB-231 cells. Moreover, FAS knockdown showed similar effect as curcumin. All these results suggested that curcumin may induce cell apoptosis via inhibiting FAS.

Topics: Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Curcumin; Drug Screening Assays, Antitumor; Fatty Acid Synthases; Female; Gene Expression; Humans; Inhibitory Concentration 50; Phosphorylation; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-bcl-2

Triple negative breast cancer (TNBC) is the hardest breast cancer subtype to treat due to lacking therapeutic target and treatment options. In this study, we found that SLUG expression was much higher in TNBC MDA-MB-231 cells than estrogen receptor alpha (ERα) positive breast cancer MCF7 cells. 4-hydroxytamoxifen (4-OHT) promoted SLUG expression, which was blocked by curcumin. Further investigation showed that SLUG activated the transcription of hexokinase-2 (HK2) by binding to HK2 promoter. SLUG knockdown inhibited HK2 expression and weakened 4-OHT resistance of MDA-MB-231 cells. Conversely, SLUG overexpression elevated HK2 level and increased 4-OHT resistance of MCF7 cells. Combination of curcumin and 4-OHT suppressed SLUG and HK2 expression, leading to mitochondrion-mediated apoptosis. These results suggested SLUG as a potential target and curcumin as a promising natural agent for overcoming 4-OHT resistance of TNBC.

Topics: Antineoplastic Agents; Apoptosis; Base Sequence; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chromatin Immunoprecipitation; Curcumin; Drug Resistance, Neoplasm; Estrogen Receptor alpha; Female; Flow Cytometry; Glycolysis; Hexokinase; Humans; Mitochondria; Molecular Sequence Data; Promoter Regions, Genetic; Snail Family Transcription Factors; Tamoxifen; Transcription Factors; Triple Negative Breast Neoplasms

The aim of this study was to evaluate therapeutic potential of curcumin-loaded poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) PHBHHx nanoparticles (CUR-NPs) and concanavaline A conjugated curcumin-loaded NPs (ConA-CUR-NPs) for breast cancer treatment. The size and zeta potential of prepared NPs were about 228 ± 5 nm and -23.3 mV, respectively. The entrapment efficiencies of polymer/drug weight ratios, 1.25CUR-NPs, 2.5CUR-NPs, 5CUR-NPs, ConA-1.25CUR-NPs, ConA-2.5CUR-NPs and ConA-5CUR-NPs were found to be ≈68, 55, 45, 70, 60 and 51%, respectively. Optimized NPs formulations in the freeze-dried form were assessed with their short-term stability for 30 days of storage at 4 °C and 25 °C. Anticancer activity of ConA-CUR-NPs was proved by MTT assay and reconfirmed by double staining and flow cytometry results. The anticancer activity of ConA-CUR-NPs was measured in human breast cancer cells (MDA-MB 231) in vitro, and the results revealed that the ConA-CUR-NPs had better tumor cells decline activity.

Topics: 3-Hydroxybutyric Acid; Antineoplastic Agents; Breast; Breast Neoplasms; Canavalia; Caproates; Cell Line, Tumor; Cell Survival; Concanavalin A; Curcumin; Delayed-Action Preparations; Drug Carriers; Female; Humans; Nanoparticles

Breast cancer is a major cause of global mortality in women. Curcumin exerts anti-proliferative, anti-migratory and apoptotic effects. The aim of this study was to evaluate gene expression involved in epithelial-mesenchymal transition (EMT). An in vitro model was developed with the MCF-10F immortalized breast epithelial cell line exposed to low radiation doses of high LET (linear energy transfer) α-particles (150 keV/µm) and cultured in the presence of 17β-estradiol (estrogen). The following cell lines were used: i) MCF-10F, normal; ii) Alpha5, pre-tumorigenic, and iii) Tumor2 derived from Alpha5 injected into the nude mice. Our previous results have shown that Alpha5 and Tumor2 increased cell proliferation, anchorage independency, invasive capabilities and tumor formation in nude mice in comparison to control. Results indicated that curcumin decreased expression of EMT-related genes in Tumor2 cell line when compared to its counterpart as E-cadherin, N-cadherin, ZEB2, Twist1, Slug, Axl, vimentin, STAT-3, fibronectin; and genes p53 and caveolin-1, as well as apoptotic genes caspase-3, caspase-8, and others such as cyclin D1 and NFκB. All these changes induced a decrease in migratory and invasive capabilities of such a cell line. Thus, it seems that curcumin may impinge upon apoptosis and metastatic properties of the malignant cells exerting antitumor activity in breast cancer cells transformed by low doses of α-particles and estrogen in vitro.

Topics: Animals; Antineoplastic Agents; Biomarkers, Tumor; Breast Neoplasms; Cell Line; Cell Movement; Cell Transformation, Neoplastic; Curcumin; Epithelial-Mesenchymal Transition; Estrogens; Female; Gene Expression Regulation, Neoplastic; Humans; Mice

A curcumin-docetaxel co-loaded nanosuspension with increased anti-breast cancer activity was developed. Curcumin is a potential anticancer agent with p-glycoprotein (p-gp) inhibiting activity may be co-administered with docetaxel as a nanosuspension to enhance its anticancer effect by increasing the oral bioavailability and decreasing drug efflux.. Nanosuspensions of curcumin and docetaxel were prepared by precipitation-homozenisation technique and evaluated for particle size, polydispersity, zeta potential and drug release. The in vitro MTT assay was conducted using MCF-7 for anti-breast cancer activity. The in vivo biodistribution by radiolabeling and tumor inhibition study was conducted in mice.. Homogenous nanosuspensions of 80 ± 20 nm were obtained with increased solubility. The drugs as nanosuspensions showed higher cytotoxicity on MCF-7 cell line compared to their suspensions due to the increased in vitro cellular uptake. Due to this increased solubility, sensitization of tumor cells and inhibition of p-gp the in-vivo results showed greater tumor inhibition rate of up to 70% in MCF-7 treated mice. Histopathological results showed higher apoptotic activity and reduced level of angiogenesis.. The in vitro and in vivo study of the nanosuspensions has shown that Co-administration of Curcumin as a p-gp inhibitor with docetaxel may have the potential to increase the anti-breast cancer efficacy of both drugs.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Availability; Breast Neoplasms; Curcumin; Docetaxel; Female; Humans; Male; MCF-7 Cells; Mice; Nanoparticles; Particle Size; Solubility; Suspensions; Taxoids; Tissue Distribution

Curcumin, a widely studied hydrophobic polyphenol with anticancer potential is loaded in gum arabic aldehyde-gelatin (GA Ald-Gel) nanogels to improve its bioavailability and therapeutic efficacy towards cancer cells. Physicochemical properties of the curcumin loaded GA Ald-Gel nanogels are investigated by different techniques including dynamic light scattering (DLS), NMR spectroscopy and scanning electron microscopy (SEM). These nanogels exhibit hydrodynamic diameter of 452±8nm with a zeta potential of -27mV. The nanogels possess an encapsulation efficiency of 65±3%. Potential of the nanogels for controlled release of curcumin is illustrated by in vitro drug release studies. Hemocompatibility and cytocompatibility of the drug loaded nanogels are evaluated. In vitro cytotoxicity of the bare and curcumin loaded nanogels are analyzed by MTT assay towards MCF-7 cells. The results manifest that curcumin loaded nanogels induce toxicity in MCF-7 cells. Confocal laser scanning microscopy (CLSM) studies indicate in vitro cellular uptake of the nanogels in MCF-7 cells. All these results prove the suitability of the curcumin loaded GA Ald-Gel nanogels for cancer therapy.

Topics: Aldehydes; Antineoplastic Agents; Breast Neoplasms; Cell Survival; Curcumin; Drug Carriers; Drug Liberation; Dynamic Light Scattering; Female; Gelatin; Gum Arabic; Humans; Magnetic Resonance Spectroscopy; MCF-7 Cells; Microscopy, Confocal; Microscopy, Electron, Scanning; Nanogels; Particle Size; Polyethylene Glycols; Polyethyleneimine

Ultrasound and microbubbles-mediated drug delivery has become a promising strategy to promote drug delivery and its therapeutic efficacy. The aim of this research was to assess the effects of microbubbles (MBs)-combined low-intensity pulsed ultrasound (LPUS) on the delivery and cytotoxicity of curcumin (Cur) to human breast cancer MDA-MB-231 cells. Under the experimental condition, MBs raised the level of acoustic cavitation and enhanced plasma membrane permeability; and cellular uptake of Cur was notably improved by LPUS-MBs treatment, aggravating Cur-induced MDA-MB-231 cells death. The combined treatment markedly caused more obvious changes of cell morphology, F-actin cytoskeleton damage and cell migration inhibition. Our results demonstrated that combination of MBs and LPUS may be an efficient strategy for improving anti-tumor effect of Cur, suggesting a potential effective method for antineoplastic therapy.

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Movement; Curcumin; Humans; Microbubbles; Ultrasonic Waves

Curcumin (CUR) and berberine (BBR) are renowned natural compounds that exhibit potent anticancer activities through distinct molecular mechanisms. However, the anticancer capacity of either CUR or BBR is limited. This prompted us to investigate the chemopreventive potential of co-treatment of CUR and BBR against breast cancers. The results showed that CUR and BBR in combination synergistically inhibited the growth of both MCF-7 and MDA-MB-231 breast cancer cells than the compounds used alone. Further study confirmed that synergistic anti-breast cancer activities of co-treatment of these two compounds was through inducing more apoptosis and autophagic cell death (ACD). The co-treatment-induced apoptosis was caspase-dependent and through activating ERK pathways. Our data also demonstrated that co-treatment of CUR and BBR strongly up-regulated phosphorylation of JNK and Beclin1, and decreased phosphorylated Bcl-2. Inhibition of JNK by SP600125 markedly decreased LC3-II and Beclin1, restored phosphorylated Bcl-2, and reduced the cytotoxicity induced by the two compounds in combination. These results strongly suggested that JNK/Bcl-2/Beclin1 pathway played a key role in the induction of ACD in breast cancer cells by co-treatment of CUR and BBR. This study provides an insight into the potential application of curcumin and berberine in combination for the chemoprevention and treatment of breast cancers.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Autophagy; Beclin-1; Berberine; Breast Neoplasms; Cell Growth Processes; Chemoprevention; Curcumin; Drug Synergism; Humans; MAP Kinase Kinase 4; MAP Kinase Signaling System; MCF-7 Cells; Proto-Oncogene Proteins c-bcl-2

A salt compound of a curcumin analogue, potassium pentagamavunon-0 (K PGV-0) has been synthesized to improve solubility of pentagamavunon-0 which has been proven to have anti-proliferative effects on several cancer cells. The purpose of this study was to investigate cytotoxic activity and metastasis inhibition by K PGV- 0 alone and in combination with achemotherapeutic agent, doxorubicin (dox), in breast cancer cells. Based on MTT assay analysis, K PGV-0 showed cytotoxic activity in T47D and 4T1 cell lines with IC50 values of 94.9 μM and 49.0±0.2 μM, respectively. In general, K PGV-0+dox demonstrated synergistic effects and decreased cell viability up to 84.7% in T47D cells and 62.6% in 4T1 cells. Cell cycle modulation and apoptosis induction were examined by flow cytometry. K PGV-0 and K PGV-0+dox caused cell accumulation in G2/M phase and apoptosis induction. Regarding cancer metastasis, while K PGV-0 alone did not show any inhibition of 4T1 cell migration, K PGV-0+dox exerted inhibition. K PGV-0 and its combination with dox inhibited the activity of MMP-9 which has a pivotal role in extracellular matrix degradation. These results show that a combination of K PGV-0 and doxorubicin inhibits cancer cell growth through cell cycling, apoptosis induction, and inhibition of cell migration and MMP-9 activity. Therefore, K PGV-0 may have potential for development as a co-chemotherapeutic agent.

Topics: Antibiotics, Antineoplastic; Apoptosis; Breast Neoplasms; Cell Cycle Checkpoints; Cell Proliferation; Curcumin; Doxorubicin; Female; Flow Cytometry; Humans; Neoplasm Metastasis; Tumor Cells, Cultured; Wound Healing

Non-invasive radiofrequency (RF) frequency may be utilized as an energy source to activate thermo-responsive nanoparticles for the controlled local delivery of drugs to cancer cells. Herein, we demonstrate that 180 ± 20 nm sized curcumin encapsulated chitosan-graft-poly(N-vinyl caprolactam) nanoparticles containing iron oxide nanoparticles (Fe3O4-CRC-TRC-NPs) were selectively internalized in cancer cells in vivo. Using an RF treatment at 80 watts for 2 min, Fe3O4-CRC-TRC-NPs, dissipated heat energy of 42 degrees C, which is the lower critical solution temperature (LCST) of the chitosan-graft-poly(N-vinyl caprolactam), causing controlled curcumin release and apoptosis to cultured 4T1 breast cancer cells. Further, the tumor localization studies on orthotopic breast cancer model revealed that Fe3O4-CRC-TRC-NPs selectively accumulated at the primary tumor as confirmed by in vivo live imaging followed by ex vivo tissue imaging and HPLC studies. These initial results strongly support the development of RF assisted drug delivery from nanoparticles for improved tumor targeting for breast cancer treatment.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Curcumin; Delayed-Action Preparations; Diffusion; Female; Magnetite Nanoparticles; Mice; Mice, Inbred BALB C; Nanocapsules; Radio Waves; Subcellular Fractions; Temperature

Development of multidrug resistance against chemotherapeutic drugs is one of the major obstacles to successful cancer therapy in the clinic. Thus far, amphiphilic polymeric micelles and chemosensitizers have been used to overcome multidrug resistance in cancer. The goals of this study were to prepare poly(ethylene glycol)-bock-poly(lactide) (PEG(2k)-PLA(5k)) micelles for co-delivery of the chemotherapeutic drug doxorubicin (DOX) with a chemosensitizer curcumin (CUR), investigate the potential of the dual drug-loaded micelles ((DOX+CUR)-Micelles) to reverse multidrug resistance, and explore the underlying mechanisms. (DOX + CUR)-Micelles were prepared using an emulsion solvent evaporation method. The cellular uptake, drug efflux, down-regulation of P-glycoprotein expression and inhibition of ATP activity of (DOX+ CUR)-Micelles were studied in drug-resistant MCF-7/ADR cells. In vitro analyses demonstrated that (DOX + CUR)-Micelles were superior to free DOX, free drug combination (DOX + CUR), and DOX-loaded micelles in inhibiting proliferation of MCF-7/ADR cells. This effect of (DOX + CUR)-Micelles was partially attributable to their highest cellular uptake, lowest efflux rate of DOX, and strongest effects on down-regulation of P-glycoprotein and inhibition of ATP activity. Additionally, (DOX+CUR)-Micelles showed increased tumor accumulation and strong inhibitory effect on tumor growth in the xenograft model of drug-resistant MCF-7/ADR cells compared to that of other drug formulations. These results indicate that (DOX + CUR)-Micelles display potential for application in the therapy of drug-resistant breast carcinoma.

Topics: Adenosine Triphosphate; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Breast Neoplasms; Curcumin; Doxorubicin; Drug Delivery Systems; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Endocytosis; Female; Humans; Inhibitory Concentration 50; MCF-7 Cells; Mice, Nude; Micelles; Particle Size; Polymers; Static Electricity; Surface-Active Agents; Xenograft Model Antitumor Assays

Curcumin is a potential agent for both the prevention and treatment of cancers. Curcumin treatment alone, or in combination with piperine, limits breast stem cell self-renewal, while remaining non-toxic to normal differentiated cells. We paired fluorescence-activated cell sorting with RNA sequencing to characterize the genome-wide changes induced specifically in normal breast stem cells following treatment with these compounds. We generated genome-wide maps of the transcriptional changes that occur in epithelial-like (ALDH+) and mesenchymal-like (ALDH-/CD44+/CD24-) normal breast stem/progenitor cells following treatment with curcumin and piperine. We show that curcumin targets both stem cell populations by down-regulating expression of breast stem cell genes including ALDH1A3, CD49f, PROM1, and TP63. We also identified novel genes and pathways targeted by curcumin, including downregulation of SCD. Transient siRNA knockdown of SCD in MCF10A cells significantly inhibited mammosphere formation and the mean proportion of CD44+/CD24- cells, suggesting that SCD is a regulator of breast stemness and a target of curcumin in breast stem cells. These findings extend previous reports of curcumin targeting stem cells, here in two phenotypically distinct stem/progenitor populations isolated from normal human breast tissue. We identified novel mechanisms by which curcumin and piperine target breast stem cell self-renewal, such as by targeting lipid metabolism, providing a mechanistic link between curcumin treatment and stem cell self-renewal. These results elucidate the mechanisms by which curcumin may act as a cancer-preventive compound and provide novel targets for cancer prevention and treatment.

Topics: Alkaloids; Antineoplastic Agents; Benzodioxoles; Breast Neoplasms; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Cell Separation; Curcumin; Female; Flow Cytometry; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; MCF-7 Cells; Piperidines; Polyunsaturated Alkamides; Sequence Analysis, RNA; Stearoyl-CoA Desaturase; Stem Cells

The role and clinical implication of ZRF1 in breast cancer are poorly understood. So this study is aimed to explore the role of ZRF1 in breast cancer progression. With this context, we first assessed its expression pattern in FFPE primary and metastasis breast tissue samples as well as from publicly available databases. Moreover, we also explored the survival status of patients from the publicly available database and interestingly discover that high expression of ZRF1 decreases the survival of estrogen-positive breast cancer patients more than estrogen-negative status patients. In the perspective of this, we evaluated the role ZRF1 in MCF-7 breast cancer cells and found that it's silencing by knockdown results in decreased cell proliferation as well as cell viability. Results also show that expression of ZRF1 is down regulated in the presence of estrogen-depleted conditions but independent of RAS/MEK as well as AKT axes. Moreover, the decrease in viability of MCF-7 cells was accompanied by induction of apoptosis and DNA damage, well-marked with upregulation of cleaved PARP and downregulation of BCL2 and H2AUbK119 levels. Furthermore, we also explored that knockdown of ZRF1 sensitises the effect of curcumin, observed with decrease in cell viability and dropping of IC50 value from 25 to 15 μM. This investigation thus shed a new light on the role on ZRF1 in breast cancer cells and hence can be exploited to design better therapeutic intervention.

Topics: Apoptosis; Breast Neoplasms; Cell Movement; Cell Proliferation; Curcumin; DNA-Binding Proteins; Female; Humans; Jumonji Domain-Containing Histone Demethylases; MCF-7 Cells; Molecular Chaperones; Oncogene Proteins; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Receptors, Estrogen; RNA-Binding Proteins

Anticancer agents consisting of hybrid molecules are used to improve effectiveness and diminish drug resistance. The current study aimed to introduce newly synthesized hetero-steroids of promising anticancer effects. Besides, the pro-apoptotic effects of new compounds were investigated extensively. Several pyrimidino-, triazolopyrimidino-, pyridazino-, and curcumin-steroid derivatives were synthesized, elucidated and confirmed using the spectral and analytical data. The synthesized hetero-steroids, compounds 9, 10, 11, 12, 13, 14, 15, 18, 20, 21, 22 and 24, were tested for their cytotoxic effects versus human breast cancer cells (MCF-7) using neutral red supravital dye uptake assay. Compound 24 (IC50=18μM) showed more inhibitory influence on MCF-7 growth. Using QRT-PCR (Quantitative real time-polymerase chain reaction), CCND1, Survivin, BCL-2, CDC2, P21 and P53, genes expression levels were investigated. The study results disclose that compounds 4, 7, 18, 24 knocked down the expression levels of CCND1, Survivin, BCL-2 and CDC2. However, P21 and P53 were up-regulated by compounds 21, 22. This study introduced promising pro-apoptotic anticancer agents acting through the modulation of key regulators of apoptosis and cell cycle genes.

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; CDC2 Protein Kinase; Curcumin; Cyclin D1; Cyclin-Dependent Kinases; Female; Humans; MCF-7 Cells; Proto-Oncogene Proteins c-bcl-2; Steroids, Heterocyclic; Tumor Suppressor Protein p53

Curcumin (diferuloyl methane) is an antioxidant that exerts antiproliferative and apoptotic effects and has anti-invasive and anti-metastatic properties. Evidence strongly implicates that epithelial-mesenchymal transition (EMT) is involved in malignant progression affecting genes such as Slug, AXL and Twist1. These genes are abnormally expressed in many tumors and favor metastasis. The purpose of this study was to determine the potential effect of curcumin on EMT, migration and invasion. Triple-positive and triple-negative breast cancer cell lines for estrogen receptor (ER), progesterone receptor (PgR) and HER/neu were used: i) MCF-10F, a normal immortalized breast epithelial cell line (negative), ii) Tumor2, a malignant and tumorigenic cell line (positive) derived from Alpha5 cell line injected into the immunologically depressed mice and transformed by 60/60 cGy doses of high LET (linear energy transfer) α particles (150 keV/µm) of radiation and estrogen, and iii) a commercially available MDA-MB‑231 (negative). The effect of curcumin (30 µM for 48 h) was evaluated on expression of EMT-related genes by RT-qPCR. Results showed that curcumin decreased E-cadherin, N-cadherin, β-catenin, Slug, AXL, Twist1, Vimentin and Fibronectin protein expression, independently of the positivity of the markers in the cell lines. Curcumin also decreased migration and invasive capabilities in comparison to their own controls. It can be concluded that curcumin influenced biochemical changes associated with EMT-related genes that seems to promote such transition and are at the core of several signaling pathways that mediate the transition. Thus, it can be suggested that curcumin is able to prevent or delay cancer progression through the interruption of this process.

Topics: Antineoplastic Agents; beta Catenin; Breast Neoplasms; Cadherins; Cell Line, Tumor; Cell Movement; Curcumin; Epithelial-Mesenchymal Transition; Female; Gene Expression Regulation, Neoplastic; Humans; Neoplasm Invasiveness; Nuclear Proteins; Snail Family Transcription Factors; Twist-Related Protein 1

A growing body of evidence suggests that cancer stem cells (CSC) have the unique biological properties necessary for tumor maintenance and spreading, and function as a reservoir for the relapse and metastatic evolution of the disease by virtue of their resistance to radio- and chemo-therapies. Thus, the efficacy of a therapeutic approach relies on its ability to effectively target and deplete CSC. In this study, we show that CSC-enriched tumorspheres from breast cancer cell lines display an increased L-Ferritin uptake capability compared to their monolayer counterparts as a consequence of the upregulation of the L-Ferritin receptor SCARA5. L-Ferritin internalization was exploited for the simultaneous delivery of Curcumin, a natural therapeutic molecule endowed with antineoplastic action, and the MRI contrast agent Gd-HPDO3A, both entrapped in the L-Ferritin cavity. This theranostic system was able to impair viability and self-renewal of tumorspheres in vitro and to induce the regression of established tumors in mice. In conclusion, here we show that Curcumin-loaded L-Ferritin has a strong therapeutic potential due to the specific targeting of CSC and the improved Curcumin bioavailability, opening up the possibility of its use in a clinical setting.

Topics: Animals; Antineoplastic Agents; Apoferritins; Breast Neoplasms; Cell Line, Tumor; Contrast Media; Curcumin; Female; Gadolinium; Heterocyclic Compounds; Humans; Magnetic Resonance Imaging; Mammary Neoplasms, Experimental; Mice, Inbred BALB C; Neoplastic Stem Cells; Organometallic Compounds; Scavenger Receptors, Class A; Spheroids, Cellular

Metastasis of lung carcinoma to breast and vice versa accounts for one of the vast majority of cancer deaths. Synergistic treatments are proven to be the effective method to inhibit malignant cell proliferation. It is highly advantageous to use the minimum amount of a potent toxic drug, such as paclitaxel (Ptx) in ng/ml together with a natural and safe anticancer drug, curcumin (Cur) to reduce the systemic toxicity. However, both Cur and Ptx suffer from poor bioavailability. Herein, a drug delivery cargo was engineered by functionalizing reduced graphene oxide (G) with an amphiphilic polymer, PF-127 (P) by hydrophobic assembly. The drugs were loaded via pi-pi interactions, resulting in a nano-sized GP-Cur-Ptx of 140 nm. A remarkably high Cur loading of 678 wt.% was achieved, the highest thus far compared to any other Cur nanoformulations. Based on cell proliferation assay, GP-Cur-Ptx is a synergistic treatment (CI < 1) and is highly potent towards lung, A549 (IC50 = 13.24 μg/ml) and breast, MDA-MB-231 (IC50 = 1.450 μg/ml) cancer cells. These positive findings are further confirmed by increased reactive oxygen species, mitochondrial membrane potential depletion and cell apoptosis. The same dose treated on normal MRC-5 cells shows that the system is biocompatible and cancerous cell-specific.

Topics: A549 Cells; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Line; Cell Line, Tumor; Cell Proliferation; Curcumin; Drug Carriers; Drug Delivery Systems; Drug Synergism; Female; Graphite; Humans; Hydrophobic and Hydrophilic Interactions; Lung Neoplasms; Membrane Potential, Mitochondrial; Nanoparticles; Oxides; Paclitaxel; Polymers; Reactive Oxygen Species

Breast cancer is the primary reason for cancer-related death in women worldwide and the development of new formulations to treat breast cancer patients is crucial. Curcumin (Cur), a natural product, exerts promising anticancer activities against various cancer types. However, its therapeutic efficacy is hindered as a result of poor water solubility, instability, and low bioavailability. The aim of this work is to assess the curative effect of a novel nanoformulation, i.e., Cur-loaded and calcium-doped dendritic mesoporous silica nanoparticles modified with folic acid (Cur-Ca@DMSNs-FA) for breast cancer therapy. The results manifested that Cur-Ca@DMSNs-FA dispersed very well in aqueous solution, released Cur with a pH-responsible profile, and targeted efficiently to human breast cancer MCF-7 cells. Further investigations indicated that Cur-Ca@DMSNs-FA effectively inhibited cell proliferation, increased intracellular ROS generation, decreased mitochondrial membrane potential, and enhanced cell cycle retardation at G2/M phase, leading to a higher apoptosis rate in MCF-7 compared to free Cur. Moreover, the Western blotting analysis demonstrated that Cur-Ca@DMSNs-FA were more active than free Cur through suppression of PI3K/AKT/mTOR and Wnt/β-catenin signaling, and activation of the mitochondria-mediated apoptosis pathway. In addition, hemolysis assay showed that the Ca@DMSNs-FA exhibited good biocompatibility. Last, in vivo studies indicated that when Cur was encapsulated in Ca@DMSNs-FA, the Cur concentration in blood serum and tumor tissues was increased after 1 h intraperitoneal injection. In conclusion, Cur-Ca@DMSNs-FA might act as a potential anticancer drug formulation for breast cancer therapy.

Topics: Antineoplastic Agents; Breast Neoplasms; Curcumin; Drug Carriers; Drug Delivery Systems; Humans; MCF-7 Cells; Nanoparticles; Phosphatidylinositol 3-Kinases; Silicon Dioxide

Global cancer burden increased to 14.1 million new cases in 2012; and breast cancer is the most common cancer in women worldwide, with nearly 1.7 million new cases diagnosed in 2012. Curcumin is the major bioactive ingredient extracted from the rhizome of the plant Curcuma longa (turmeric). Paclitaxel is a microtubule-stabilizing agent originally isolated from the bark of Taxus brevifolia. Curcumin and paclitaxel were evaluated with two human breast cancer cell lines as the luminal MCF-7 and the basal-like MDA-MB-231 that are either positive or negative for hormonal receptors estrogen receptor, progesterone receptor and HER2, respectively. Results indicated that curcumin combined with paclitaxel decreased c-Ha-Ras, Rho-A, p53 and Bcl-xL gene expression in comparison to control and substances alone in MCF-7 cell line. These two substances alone and combined decreased gene expression of Bcl-2 and NF-κB. However, CCND1 increased when both substances were combined in MCF-7 cells. Such substances decreased Bcl-2 and increased Bax protein expression. However, curcumin alone decreased IκBα and Stat-3 gene expression. Paclitaxel alone and combined increased IκBα and Stat-3. Curcumin alone and combined with paclitaxel increased p53, Bid, caspase-3, caspase-8 and Bax gene expression in MDA-MB-231, whereas Bcl-xL decreased such expression in MDA-MB-231 cells. When paclitaxel and curcumin were combined the expression of Bcl-2 protein was decreased. However, either substance alone and combined increased Bax protein expression corroborating the apoptotic effect of these substances. It can be concluded that curcumin may be of considerable value in synergistic therapy of breast cancer reducing the associated toxicity with use of drugs.

Topics: Antineoplastic Combined Chemotherapy Protocols; bcl-X Protein; BH3 Interacting Domain Death Agonist Protein; Breast Neoplasms; Carcinogenesis; Caspase 3; Caspase 8; Cell Line, Tumor; Curcumin; Cyclin D1; Female; Humans; MCF-7 Cells; NF-KappaB Inhibitor alpha; Paclitaxel; Proto-Oncogene Proteins p21(ras); rhoA GTP-Binding Protein; STAT3 Transcription Factor; Tumor Suppressor Protein p53

Topics: Antineoplastic Agents; Apoptosis; Breast; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Curcumin; Delayed-Action Preparations; Emulsions; Female; Humans; Ovarian Neoplasms; Ovary; Tocotrienols; Vitamins

Although curcumin (CUR) can inhibit proliferation and induce apoptosis of tumors, the poor water solubility restricted its clinical application. The aim of this study was to improve the aqueous solubility of CUR and make more favorable changes to bioactivity by preparing curcumin-loaded phospholipid-sodium deoxycholate-mixed micelles (CUR-PC-SDC-MMs). CUR-PC-SDC-MMs were prepared by the thin-film dispersion method. Based on the results of single factor exploration, the preparation technology was optimized using the central composite design-response surface methodology with drug loading and entrapment efficiency (EE%) as indicators. The images of transmission electron microscopy showed that the optimized CUR-PC-SDC-MMs were spherical and well dispersed. The average size of the mixed micelles was 66.5 nm, the zeta potential was about -26.96 mV and critical micelle concentration was 0.0087 g/l. CUR was encapsulated in PC-SDC-MMs with loading capacity of 13.12%, EE% of 87.58%, and the solubility of CUR in water was 3.14 mg/ml. The release results in vitro showed that the mixed micelles presented sustained release behavior compared to the propylene glycol solution of CUR. The IC50 values of CUR-loaded micelles and free drug in human breast carcinoma cell lines were 4.10 μg/ml and 6.93 µg/ml, respectively. It could be concluded from the above results that the CUR-PC-SDC-MMs system might serve as a promising nanocarrier to improve the solubility and bioactivity of CUR.

Topics: Antineoplastic Agents; Breast Neoplasms; Chemistry, Pharmaceutical; Curcumin; Delayed-Action Preparations; Deoxycholic Acid; Drug Carriers; Female; Humans; Inhibitory Concentration 50; MCF-7 Cells; Micelles; Microscopy, Electron, Transmission; Particle Size; Phospholipids; Solubility

Antimetabolites have proven successful as therapeutics for advanced-stage breast cancers, but are often accompanied by severe side effects that can limit treatment regimens. 5-Fluorouracil (5-FU), an antimetabolite that inhibits cell proliferation, has served an important role in standard chemotherapy protocols for a variety of solid tumors. Although reasonable response rates have been reported for 5-FU, continued exploration is necessary to improve clinical outcomes and reduce cytotoxic side effects that are an inherent problem for chemotherapeutic interventions. Because of its diverse anticancer properties, we explored whether by combining the natural product curcumin with 5-FU, synergistic improvements in preventing breast cancer cell proliferation and/or provide protection against 5-FU-induced cytotoxicity could be achieved. Indeed both curcumin and 5-FU inhibit DNA synthesis in MDA-MB-231 cells using BrdU incorporation assays; however, combined treatment showed no synergistic improvement. We next established the cytotoxicity profile for 5-FU in MDA-MB-231 cells using a tetrazolium-based cell viability assay and obtained an LD50 value of 28 μM. When 5-FU incubations were repeated with the addition of curcumin, the LD50 value increased to 200-300 μM, representing a 7-10-fold protection by curcumin against 5-FU cytotoxicity. These findings suggest that the addition of curcumin as an adjuvant therapy during 5-FU treatment might enhance the chemotherapeutic effectiveness of 5-FU by protecting normal cells from reduced viability and thus permitting higher dosing or longer treatment times. This would be especially important to those individuals who are plagued with severe cytotoxicities and require frequent interruptions, or even early termination of their treatment regimens.

Topics: Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; Female; Fluorouracil; Humans

Tumour progression is associated with immune-suppressive conditions that facilitate the escape of tumour cells from the regimen of immune cells, subsequently paralysing the host defence mechanisms. Induction of CD4(+)  CD25(+)  FoxP3(+) T regulatory (Treg) cells has been implicated in the tumour immune escape mechanism, although the novel anti-cancer treatment strategies targeting Treg cells remain unknown. The focus of this study is to define the interaction between tumour and immune system, i.e. how immune tolerance starts and gradually leads to the induction of adaptive Treg cells in the tumour microenvironment. Our study identified hyperactivated mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) -signalling as a potential target for reversing Treg cell augmentation in breast cancer patients. In more mechanistic detail, pharmacological inhibitors of MEK/ERK signalling inhibited transforming growth factor-β (TGF-β) production in tumour cells that essentially blocked TGF-β-SMAD3/SMAD4-mediated induction of CD25/interleukin-2 receptor α on CD4(+) T-cell surface. As a result high-affinity binding of interleukin-2 on those cells was prohibited, causing lack of Janus kinase 1 (JAK1)/JAK3-mediated signal transducer and activator of transcription 3 (STAT3)/STAT5 activation required for FoxP3 expression. Finally, for a more radical approach towards a safe MEK inhibitor, we validate the potential of multi-kinase inhibitor curcumin, especially the nano-curcumin made out of pure curcumin with greater bioavailability; in repealing tumour-shed TGF-β-induced Treg cell augmentation.

Topics: Animals; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Case-Control Studies; Chemistry, Pharmaceutical; Coculture Techniques; Curcumin; Dose-Response Relationship, Drug; Female; Forkhead Transcription Factors; Humans; Interleukin-2 Receptor alpha Subunit; MAP Kinase Kinase Kinases; Mice, Inbred BALB C; Nanoparticles; Paracrine Communication; Protein Kinase Inhibitors; Signal Transduction; Smad Proteins; STAT Transcription Factors; T-Lymphocytes, Regulatory; Time Factors; Transforming Growth Factor beta; Tumor Cells, Cultured; Tumor Escape; Tumor Microenvironment

In order to improve curcumin's low water-solubility and selective delivery to cancer, we reported ligand-mediated micelles based on a Y-shaped biotin-poly (ethylene glycol)-poly (epsilon-caprolactone)2 (biotin-PEG-PCL2) copolymer. Its structure was characterized by (1)H NMR. The blank and drug-loaded micelles obtained by way of thin-film hydration were characterized by dynamic light scattering, X-ray diffraction, infrared spectroscopy and hemolytic test. Curcumin was loaded into micelles with a high encapsulating efficiency (93.83%). Curcumin's water-solubility was enhanced 170,400 times higher than free curcumin. Biotin-PEG-PCL2 micelles showed slower drug release in vitro than H2N-PEG-PCL2 micelles. In vitro cellular uptake and cytotoxicity tests showed that higher dosage of curcumin might overcome the effect of slow release on cytotoxicities because of its higher uptake induced by biotin, resulting in higher anticancer activities against MDA-MB-436 cells. In brief, Y-shaped biotin-PEG-PCL2 is a promising delivery carrier for anticancer drug.

Topics: Antineoplastic Agents; Biotin; Breast Neoplasms; Cell Proliferation; Curcumin; Drug Carriers; Drug Delivery Systems; Ethylene Glycols; Female; Humans; Micelles; Molecular Structure; Polyesters; Polymers; Tumor Cells, Cultured

Although doxorubicin (Dox)-induced cardiac toxicity and pegylated liposomal doxorubicin (PLD)-induced hand-foot syndrome (HFS) were reported to be correlated with reactive oxygen species (ROS) generation, there is no effective preventive treatment at present. Therefore, the aim of this study was to investigate whether antioxidants-resveratrol (RSVL), tetrahydroxystilbene glucoside (THSG), curcumin, and the ethanolic extract of Antrodia cinnamomea (EEAC)-have the ability to reduce Dox-induced ROS and have a synergistic anticancer effect with Dox that could prevent those side effects and enhance the efficacy of cancer treatment.. 3T3 normal cells were used as a model to evaluate the effects of these antioxidants in reducing ROS accumulation. Furthermore, the synergistic anticancer effect of antioxidants with Dox on the MCF-7 breast cancer model was also evaluated.. Pretreatment of cells with RSVL, curcumin, and EEAC increased the cell antioxidant ability by improving the activity of superoxide dismutase (SOD), prevented or limited intracellular damage, and ameliorated the harmful effects of ROS. Additionally, RSVL, curcumin, and EEAC had synergistic effects with Dox against MCF-7 breast cancer cells.. RSVL, curcumin, and EEAC have the potential to be clinically applied to prevent cardiac toxicity and HFS and enhance the anticancer efficiency of Dox.

Topics: 3T3 Cells; Animals; Antibiotics, Antineoplastic; Antioxidants; Antrodia; Breast Neoplasms; Complementary Therapies; Curcumin; Doxorubicin; Drug Synergism; Female; Glucosides; Humans; MCF-7 Cells; Mice; Plant Extracts; Reactive Oxygen Species; Resveratrol; Stilbenes; Superoxide Dismutase

Albumin is an ideal carrier for hydrophobic drugs. This paper reports a facile route to develop human serum albumin (HSA)-curcumin (CCM) nanoparticles, in which β-mercaptoethanol (β-ME) acted as an inducer and CCM acted as a bridge. Fluorescence quenching and conformational changes in HSA-CCM nanoparticles occurred during assembly. Disulfide bonds and hydrophobic interactions may play a key role in assembly. HSA-CCM nanoparticles were about 130 nm in size, and the solubility of CCM increased by more than 500 times. The HSA-CCM nanoparticles could accumulate at the cytoplasm of tumor cells and target the tumor tissues. Therefore, HSA nanoparticles fabricated by β-ME denaturation are promising nanocarriers for hydrophobic substances from chemotherapy drugs to imaging probes.

Topics: Animals; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Curcumin; Drug Carriers; Humans; Hydrophobic and Hydrophilic Interactions; MCF-7 Cells; Mercaptoethanol; Mice, Inbred ICR; Nanoparticles; Particle Size; Serum Albumin

In this work the selective uptake of native horse spleen ferritin and apoferritin loaded with MRI contrast agents has been assessed in human breast cancer cells (MCF-7 and MDA-MB-231). The higher expression of L-ferritin receptors (SCARA5) led to an enhanced uptake in MCF-7 as shown in T2 and T1 weighted MR images, respectively. The high efficiency of ferritin internalization in MCF-7 has been exploited for the simultaneous delivery of curcumin, a natural therapeutic molecule endowed with antineoplastic and anti-inflammatory action, and the MRI contrast agent Gd-HPDO3A. This theranostic system is able to treat selectively breast cancer cells over-expressing ferritin receptors. By entrapping in apoferritin both Gd-HPDO3A and curcumin, it was possible to deliver a therapeutic dose of 167 μg ml(-1) (as calculated by MRI) of this natural drug to MCF-7 cells, thus obtaining a significant reduction of cell proliferation.

Topics: Agar; Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Apoferritins; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Contrast Media; Curcumin; Drug Carriers; Female; Ferritins; Horses; Humans; Iron-Binding Proteins; Magnetic Resonance Imaging; MCF-7 Cells; Receptors, Cell Surface; Scavenger Receptors, Class A; Spleen; Temperature; Theranostic Nanomedicine

Application of nanoparticles has recently promising results for water insoluble agents like curcumin. In this study, we synthesized polymeric nanoparticle-curcumin (PNPC) and then showed its efficiency, drug loading, stability, and safety. Therapeutic effects of PNPC were also assessed on two cell lines and in an animal model of breast cancer. PNPC remarkably suppressed mammary and hepatocellular carcinoma cells proliferation (P < 0.05). Under the dosing procedure, PNPC was safe at 31.25 mg/kg and lower doses. Higher doses demonstrated minimal hepatocellular and renal toxicity in paraclinical and histopathological examinations. Tumor take rate in PNPC-treated group was 37.5% compared with 87.5% in control (P < 0.05). Average tumor size and weight were significantly lower in PNPC group than control (P < 0.05). PNPC increased proapoptotic Bax protein expression (P < 0.05). Antiapoptotic Bcl-2 protein expression, however, was lower in PNPC-treated animals than the control ones (P < 0.05). In addition, proliferative and angiogenic parameters were statistically decreased in PNPC-treated animals (P < 0.05). These results highlight the suppressing role for PNPC in in vitro and in vivo tumor growth models. Our findings provide credible evidence for superior biocompatibility of the polymeric nanocarrier in pharmacological arena together with an excellent tumor-suppressing response.

Topics: Animals; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Carcinoma, Hepatocellular; Cell Line; Cell Line, Tumor; Cell Proliferation; Curcumin; Drug Carriers; Drug Stability; Female; Humans; Liver Neoplasms; Mice; Mice, Inbred BALB C; Micelles; Nanoparticles; Polymers

Breast adenocarcinoma cell line MDA-MB-231, even if it expresses low levels of E-cadherin, still readily form multicellular aggregates of cells, namely spheroids. Curcumin is a diarylheptanoid antitumoral drug while it significantly inhibits cell migration, invasion, and colony formation in vitro and reduces tumor growth and liver metastasis in vivo. Curcumin photoactivation may enhance antiapoptotic role against cancer cells.. To evaluate the effect of low curcumin concentrations, ranged from 1.9 to 15 μM, with and without photoactivation, using a manufactured 670 nm LED-matrix. A secondary aim was to evaluate the ideal method to produce easy-to-use tumor cell spheroids, comparing two low adherence plate supports.. Breast adenocarcinoma cell line MDA-MB-231 were cultured according to 2D monolayer and 3D spheroid models then submitted to normal and photoactivated curcumin in micromolar concentrations. MTT assay was used to evaluate cell viability following curcumin application on cells. On 2D cell cultures, curcumin inhibits cell tumor development and proliferation at concentrations of 15 μM, with a viability of 65.7% at 48 hours incubation time. A decreased viability up to 25% for a concentration of 15 μM was recorded following photoactivation and cytotoxic action on breast cancer tumor cell line continued at concentrations of 7.5 and 3.75 μM. Curcumin photoactivation increases pro-apoptotic effects in both 2D and 3D tumor cell culture models and also responsiveness to curcumin is slightly reduced in spheroid-like structures. Thus, 3D tumor cell culture systems appear to be the ideal environment for in vitro assays regarding anticancer drug effects on cell viability.

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Adhesion; Cell Culture Techniques; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Curcumin; Female; Humans; Light; Neoplasm Metastasis; Phototherapy; Polymers; Spheroids, Cellular

Amplification of the HER2 gene (also known as neu or ErbB2) or overexpression of HER2 protein has become a solicitous therapeutic target in metastatic and clinical drug-resistance cancer. In our present work, a new series of curcumin derivatives were designed and synthesized using curcumin as model. Here, we evaluated whether curcumin derivatives have better efficiency to degrade HER2 than curcumin. Among these test compounds, pculin02H had better efficiency to inhibit the expression of HER2 than curcumin. Moreover, pculin02H preferentially suppressed the growth of HER2-overexpressing cancer cell lines. Pculin02H induced G2/M cell cycle arrest followed by apoptosis. Interestingly, our results suggested that a posttranslational mechanism contributed to pculin02H-induced HER2 depletion in HER2-overexpressing cancer cells. We found that pculin02H significantly enhanced the antitumor efficacy of clinical drugs on HER2-overexpressing cancer cells as well as efficiently reduced HER2-induced drug resistance. These findings may provide an alternative preventive or therapeutic strategy against HER2-overexpressing cancer cells.

Topics: Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Curcumin; Drug Resistance; Female; G2 Phase Cell Cycle Checkpoints; Gene Expression Regulation, Neoplastic; Humans; MCF-7 Cells; Receptor, ErbB-2

Breast cancer is considered the most common cancer for women worldwide and it is now the second leading cause of cancer-related deaths among females in the world. Since breast cancer is highly resistant to chemotherapy, alternative anticancer strategies have been developed. In particular, many studies have demonstrated that curcumin, a derivative of turmeric, can be used as natural agent in treatment of some types of cancer by playing antiproliferative and antioxidant effects. In our study, we assessed the antitumor activities of curcumin in ER-negative human breast cancer cell line resistant to chemotherapy, MDA.MB231 by in vitro and in vivo experiments. In vitro data allowed us to demonstrate that curcumin played a role in regulation of proliferation and apoptosis in MDA.MB231 cells. In vivo, by generation of mouse model of breast cancer, we showed that treatment of curcumin inhibited tumor growth and angiogenesis. Specifically, we showed that curcumin is able to deregulate the expression of cyclin D1, PECAM-1, and p65, which are regulated by NF-κB. Our data demonstrated that curcumin could be used as an adjuvant agent to chemotherapy in treatment of triple negative breast cancer.

Topics: Animals; Apoptosis; Breast Neoplasms; Cell Proliferation; Curcumin; Cyclin D1; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Humans; Mice; Neovascularization, Pathologic; NF-kappa B; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays

Curcumin has been shown to mitigate cancer phenotypes such as invasive migration, proliferation, and survival by disrupting numerous signaling pathways. Our previous studies showed that curcumin inhibits integrin β4 (ITG β4)-dependent migration by blocking interaction of this integrin with growth factor receptors in lipid rafts. In the current study, we investigated the possibility that curcumin inhibits ITG β4 palmitoylation, a post-translational modification required for its lipid raft localization and signaling activity. We found that the levels of ITG β4 palmitoylation correlated with the invasive potential of breast cancer cells, and that curcumin effectively reduced the levels of ITG β4 palmitoylation in invasive breast cancer cells. Through studies of ITG β4 palmitoylation kinetics, we concluded curcumin suppressed palmitoylation independent of growth factor-induced phosphorylation of key ITG β4 Ser and Tyr residues. Rather, curcumin blocked autoacylation of the palmitoyl acyltransferase DHHC3 that is responsible for ITG β4 palmitoylation. Moreover, these data reveal that curcumin is able to prevent the palmitoylation of a subset of proteins, but not indiscriminately bind to and block all cysteines from modifications. Our studies reveal a novel paradigm for curcumin to account for much of its biological activity, and specifically, how it is able to suppress the signaling function of ITG β4 in breast cancer cells.

Topics: Acylation; Acyltransferases; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Curcumin; Female; Humans; Integrin beta4; Lipoylation; Phosphorylation; Signal Transduction

Curcumin, a lipid-soluble compound extracted from the plant Curcuma Longa, has been found to exert immunomodulatory effects via macrophages. However, most studies focus on the low bioavailability issue of curcumin by nano and microparticles, and thus the role of macrophages in the anticancer mechanism of curcumin has received little attention so far. We have previously shown the potential biocompatibility, biodegradability and anti-cancer effects of dendrosomal curcumin (DNC). In this study, twenty-seven BALB/c mice were equally divided into control as well as 40 and 80 mg/kg groups of DNC to investigate the involvement of macrophages in the antitumor effects of curcumin in a typical animal model of metastatic breast cancer. At the end of intervention, the tumor volume and weight were significantly reduced in DNC groups compared to control (P<0.05). Histopathological data showed the presence of macrophages in tumor and spleen tissues. Real-time PCR results showed that DNC increased the expression of STAT4 and IL-12 genes in tumor and spleen tissues in comparison with control (P<0.05), referring to the high levels of M1 macrophages. Furthermore treatment with DNC decreased STAT3, IL-10 and arginase I gene expression (P<0.05), indicating low levels of M2 macrophage. The results confirm the role of macrophages in the protective effects of dendrosomal curcumin against metastatic breast cancer in mice.

Topics: Animals; Antineoplastic Agents; Apoptosis; Blotting, Western; Breast Neoplasms; Cell Proliferation; Curcumin; Drug Carriers; Female; Humans; Macrophages; Mice; Mice, Inbred BALB C; Nanocapsules; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; STAT3 Transcription Factor; Tumor Burden; Tumor Cells, Cultured; Tumor Microenvironment; Xenograft Model Antitumor Assays

The formation of a new blood vessel is stimulated by angiogenic factors. Curcumin, which is the active ingredient of the spice plant Curcuma longa L and is used as food and traditional medicine, has shown anticancer effects against different types of cancers. We evaluated the effects of curcumin on angiogenesis/pro-angiogenic factors in a mouse model of human breast cancer. Cell viability was measured by the MTT assay after curcumin treatment in triple-negative breast cancer cells (MDA-MB-231). For the in vivo study, human breast cancer was induced in athymic mice and treated with 300 mg/kg/day of curcumin administered intraperitoneally. Tumor size was measured weekly, and the animals underwent single photon emission computed tomography (SPECT) scanning with Tc-99m tagged VEGF-c to detect the in vivo expression of VEGFR2/3. In addition, the expression of proangiogenic/ growth factors in the tumor extracts was evaluated by a membrane antibody array. Histological analysis was performed to confirm the effect of curcumin on neovascularization. The MTT assay showed that curcumin significantly reduced the cell viability of MDA-MB-231 cells. In breast cancer xenografts, curcumin treatment led to a decrease in tumor volume and cell proliferation (Ki-67) compared with the vehicle treated group. Tc-99m-HYNIC-VEGF-c-SPECT imaging showed decreased uptake to the tumor, which may indicate a lower expression of VEGFR2/3 in curcumin treated tumors; however, a statistically significant difference was not achieved (p>0.05). Additionally, curcumin treatment showed a significantly low level of expression of pro-angiogenic factors (p<0.05) and a decrease in micro-vessel density (vWF) in animals compared with that of vehicle treated tumors. In conclusion, curcumin treatment showed effectiveness in reducing tumor growth and cell proliferation, as well as in the inhibition of angiogenesis.

Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Curcumin; Female; Heterografts; Humans; Models, Biological; Neovascularization, Pathologic

Breast cancer stem cells are well known to resist the traditional methods like chemo and radio therapy. Aldehyde dehydrogenase 1 (ALDHIA1) and glycogen synthase kinase-3 β (GSK-3β) are the two selected proteins for study, due to their overexpression and upregulation in breast cancer cells. Curcumin, the yellow pigment of the spice turmeric, is widely reported as an antioxidant and acts as a synergist along with traditional drugs. Under hypoxic conditions, it gets converted to free radical which causes apoptosis. Three naturally occurring curcuminoids, i.e. curcumin, demethoxycurcumin, and bisdemethoxycurcumin along with five derivatives/analogues of curcumin, viz. 4,4'-di-O-(carboxy-methyl)-curcumin, 4-O-(2-hydroxyethyl)curcumin, 4,4'-di-O-allyl-curcumin, 4,4'-di-O-(acetyl)-curcumin, and 3,3'-bisdemethylcurcumin were synthesized and evaluated for their anti-breast cancer potential by docking simulation and assessment of their antioxidant character, studied via 2, 2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS(·+)) radical cation scavenging assay, 2,2-diphenyl-1-picrylhydrazyl (DPPH·) radical, and ferric reducing ability potential (FRAP) assay. A co-relation between structure and activity of curcuminoids/its analogues and derivatives has been worked out.

Topics: Aldehyde Dehydrogenase 1 Family; Antioxidants; Breast Neoplasms; Curcumin; Drug Resistance, Neoplasm; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Isoenzymes; Molecular Docking Simulation; Molecular Targeted Therapy; Protein Conformation; Retinal Dehydrogenase

Curcumin (as a natural reductant material) was utilized for green reduction and functionalization of chemically exfoliated graphene oxide (GO) sheets. The π-π attachment of the curcumin molecules onto the curcumin-reduced graphene oxide (rGO) sheets was confirmed by Raman and Fourier transform infrared spectroscopies. Zeta potential of the GO sheets decreased from about -40 mV to -20 mV, after the green reduction and functionalization. The probable cytotoxicity of the curcumin-rGO sheets was studied through their interactions with two human breast cancer cell lines (MDA-MB-231 and SKBR3 cell lines) and a normal cell line (mouse fibroblast L929 cell line). The curcumin-rGO sheet with concentrations <70 μg/mL in the cell culture medium, not only exhibited no significant toxicity and/or cell morphological changes, but also caused some cell growths (~25% after 48 h incubation time). Nevertheless, at 70 μg/mL, initiation of some cell morphological changes was observed. At higher concentrations (e.g., 100 μg/mL), some slight cytotoxic effects (resulting in ~15-25% cell destruction) were detected by MTT assay. In addition, the interaction of the rGO sheets and cells resulted in apoptosis as well as morphological transformation of the cells (from elongated to roundup morphology). These results indicated the concentration-dependent toxicity of functionalized-rGO nanomaterials (here, curcumin-rGO) at the threshold concentration of ~100 μg/mL.

Topics: Breast Neoplasms; Cell Line, Tumor; Curcumin; Female; Graphite; Humans; Oxides; Spectrum Analysis

Combination therapy using two or more small molecule inhibitors of aberrant signaling cascade in aggressive breast cancers is a promising therapeutic strategy over traditional monotherapeutic approaches. Here, we have studied the synergistic mechanism of resveratrol and curcumin induced apoptosis using in vitro (cigarette smoke condensate mediated transformed breast epithelial cell, MCF-10A-Tr) and in vivo (tumor xenograft mice) model system. Resveratrol exposure increased the intracellular uptake of curcumin in a dose dependent manner and caused apoptosis in MCF-10A-Tr cells. Approximately, ten fold lower IC50 value was noted in cells treated with the combination of resveratrol (3μM) and curcumin (3μM) in comparison to 30μM of resveratrol or curcumin alone. Resveratrol+curcumin combination caused apoptosis by increasing Bax/Bcl-xL ratio, Cytochrome C release, cleaved product of PARP and caspase 3 in cells. Interestingly, this combination unaltered the protein expressions of WNT-TCF and Notch signaling components, β-catenin and cleaved notch-1 val1744, respectively. Furthermore, the combination also significantly decreased the intermediates of Hedgehog-Gli cascade including SMO, SHH, Gli-1, c-MYC, Cyclin-D1, etc. and increased the level of p21(Waf/Cip1) in vitro and in vivo. A significant reduction of Gli- promoter activity was noted in combinational drug treated cells in comparison to individual drug treatment. Un-alteration of the expressions of the above proteins and Gli1 promoter activity in p21(Waf/Cip1) knockout cells suggests this combination caused apoptosis through p21(Waf/Cip1). Thus, our findings revealed resveratrol and curcumin synergistically caused apoptosis in cigarette smoke induced breast cancer cells through p2(Waf/Cip1) mediated inhibition of Hedgehog-Gli cascade.

Topics: Animals; Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; bcl-X Protein; Breast Neoplasms; Cell Line; Cell Transformation, Neoplastic; Curcumin; Cyclin-Dependent Kinase Inhibitor p21; Drug Synergism; Epithelial Cells; Female; Hedgehog Proteins; Humans; Immunoblotting; Mice, Inbred BALB C; Microscopy, Fluorescence; Nicotiana; Resveratrol; RNA Interference; Signal Transduction; Smoke; Stilbenes; Transcription Factors; Xenograft Model Antitumor Assays; Zinc Finger Protein GLI1

Cancer cells with stem cell-like properties contribute to the development of resistance to chemotherapy and eventually to tumor relapses. The current study investigated the potential of curcumin to reduce breast cancer stem cell (BCSC) population for sensitizing breast cancer cells to mitomycin C (MMC) both in vitro and in vivo. Curcumin improved the sensitivity of paclitaxel, cisplatin, and doxorubicin in breast cancer cell lines MCF-7 and MDA-MB-231, as shown by the more than 2-fold decrease in the half-maximal inhibitory concentration of these chemotherapeutic agents. In addition, curcumin sensitized the BCSCs of MCF-7 and MDA-MB-231 to MMC by 5- and 15-fold, respectively. The BCSCs could not grow to the fifth generation in the presence of curcumin and MMC. MMC or curcumin alone only marginally reduced the BCSC population in the mammospheres; however, together, they reduced the BCSC population in CD44+CD24-/low cells by more than 75% (29.34% to 6.86%). Curcumin sensitized BCSCs through a reduction in the expression of ATP-binding cassette (ABC) transporters ABCG2 and ABCC1. We demonstrated that fumitremorgin C, a selective ABCG2 inhibitor, reduced BCSC survival to a similar degree as curcumin did. Curcumin sensitized breast cancer cells to chemotherapeutic drugs by reducing the BCSC population mainly through a reduction in the expression of ABCG2.

Topics: ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Breast Neoplasms; Cell Proliferation; Curcumin; Doxorubicin; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Humans; Indoles; MCF-7 Cells; Mitomycin; Neoplasm Proteins; Neoplasm Recurrence, Local; Neoplastic Stem Cells

Increasing evidence support the critical roles of active stromal fibroblasts in breast cancer development and spread. However, the mediators and the mechanisms of regulation are still not well defined. We have shown here that the tumor suppressor p16(INK4A) protein inhibits the pro-carcinogenic effects of breast stromal fibroblasts through repressing the expression/secretion of IL-6. Indeed, p16(INK4A) suppresses IL-6 at the mRNA and protein levels. This effect is mediated trough miR-146b-5p, which inhibits IL-6 expression through a specific sequence at the IL-6 3'UTR. In addition, we present clear evidence that miR-146b-5p inhibition is sufficient to transactivate breast stromal fibroblasts, which promote epithelial-to-mesenchymal-transition in breast cancer cells in a paracrine manner. By contrast, ectopic expression of miR-146b-5p in active fibroblasts abrogated their pro-carcinogenic effects. The physiological importance of miR-146b-5p inhibition was revealed by showing that the levels of pre-miR-146b-5p as well as its mature form are reduced in cancer-associated fibroblasts as compared with their normal adjacent counterparts from cancer-free tissues isolated from the same patients. Interestingly, treatment of active breast stromal fibroblasts with curcumin increased the level of the p16(INK4A) coding CDKN2A mRNA and miR-146b-5p and suppressed IL-6, which confirms the repressive effect of these two tumor suppressor molecules on IL-6, and shows the possible "normalization" of cancer-related active fibroblasts. These results show that miR-146b-5p has non-cell-autonomous tumor suppressor function through inhibition of IL-6, suggesting that targeting this microRNA in breast stromal fibroblasts could be of great therapeutic value.

Topics: 3' Untranslated Regions; Antineoplastic Agents; Breast; Breast Neoplasms; Cell Line, Tumor; Cells, Cultured; Curcumin; Cyclin-Dependent Kinase Inhibitor p16; Epithelial-Mesenchymal Transition; Female; Fibroblasts; Gene Expression Regulation; Humans; Immunoblotting; Interleukin-6; MicroRNAs; Models, Genetic; Reverse Transcriptase Polymerase Chain Reaction; Stromal Cells

Breast cancer chemoprevention has become increasingly important in India as it faces a potential breast cancer epidemic over the next decade. Curcumin, the active ingredient in turmeric is a well known chemopreventive agent that possesses various therapeutic properties including antioxidants and anti-inflammatory effects. In the present study, we have investigated the inhibitory effects of BDMC-A, an analog of curcumin, on invasion, angiogenesis and metastasis markers using in vitro with MCF-7 cells and in silico studies, hence proved that BDMC-A has more potential than curcumin. Mechanistic studies revealed that BDMC-A might have exerted its activity by inhibiting metastatic and angiogenic pathways by modulating the expression of proteins upstream to NF-κB (TGF-β, TNF-α, IL-1β and c-Src), and NF-κB signaling cascade (c-Rel, COX-2, MMP-9, VEGF, IL-8) and by upregulating TIMP-2 levels. An in silico molecular docking study with NF-κB revealed that the docking score and interaction of BDMC-A with NF-κB-DNA binding was more efficient when compared to curcumin. Our overall results showed that BDMC-A more effectively inhibited invasion, angiogenesis and metastasis markers compared to curcumin. The activity can be attributed to the presence of hydroxyl group in the ortho position in its structure. Further research are going on to prove its potential as a therapeutic agent for breast cancer.

Topics: Anticarcinogenic Agents; Breast Neoplasms; Computer Simulation; Curcumin; Female; Humans; MCF-7 Cells; Molecular Docking Simulation; Neoplasm Invasiveness; Neoplasm Metastasis; Neovascularization, Pathologic; NF-kappa B; Signal Transduction

Poly(ADP-ribose) polymerase (PARP) inhibitor has shown promising responses in homologous recombination (HR) repair-deficient cancer cells. More specifically, targeting HR pathway in combination with PARP inhibitor has been an effective chemotherapy strategy by so far. Curcumin has been recognized as anticancer agents for several types of cancers. Here, we demonstrate that curcumin inhibits a critical step in HR pathway, Rad51 foci formation, and accumulates γ-H2AX levels in MDA-MB-231 breast cancer cells. Curcumin also directly reduces HR and induces cell death with cotreatment of PARP inhibitor in MDA-MB-231 breast cancer cells. Moreover, curcumin, when combined with ABT-888, could effectively delayed breast tumor formation in vivo. Our study indicates that cotreatment of curcumin and PARP inhibitor might be useful for the combination chemotherapy for aggressive breast cancer treatment as a natural bioactive compound.

Topics: Animals; Antineoplastic Agents; Benzimidazoles; Breast Neoplasms; Cell Line, Tumor; Curcumin; DNA Repair; Female; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Green Fluorescent Proteins; Histones; Humans; MCF-7 Cells; Mice; Mice, Nude; Neoplasm Transplantation; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Rad51 Recombinase; Recombination, Genetic

Curcumin is conjugated to gum arabic, a highly water soluble polysaccharide to enhance the solubility and stability of curcumin. Conjugation of curcumin to gum arabic is confirmed by (1)H NMR, fluorescence and UV spectroscopy studies. The conjugate self assembles to spherical nano-micelles (270 ± 5 nm) spontaneously, when dispersed in aqueous medium. Spherical morphology of the self assembled conjugate is evidenced by field emission scanning electron microscopy and transmission electron microscopy. The self assembly of the amphiphilic conjugate into micelle in aqueous medium significantly enhances the solubility (900 fold of that of free curcumin) and stability of curcumin in physiological pH. The anticancer activity of the conjugate micelles is found to be higher in human hepatocellular carcinoma (HepG2) cells than in human breast carcinoma (MCF-7) cells. The conjugate exhibits enhanced accumulation and toxicity in HepG2 cells due to the targeting efficiency of the galactose groups present in gum arabic.

Topics: Antineoplastic Agents; Breast Neoplasms; Carcinoma, Hepatocellular; Curcumin; Drug Carriers; Female; Gum Arabic; Hep G2 Cells; Humans; Liver; Liver Neoplasms; MCF-7 Cells; Micelles

Heme oxygenase (HO)-1 is an oxidative stress-response enzyme which catalyzes the degradation of heme into bilirubin, ferric ion, and carbon monoxide (CO). Induction of HO-1 was reported to have antitumor activity; the inhibitory mechanism, however, is still unclear. In the present study, we found that treatment with [Ru(CO)3Cl2]2 (RuCO), a CO-releasing compound, reduced the growth of human MCF7 and MDA-MB-231 breast cancer cells. Analysis of growth-related proteins showed that treatment with RuCO down-regulated cyclinD1, CDK4, and hTERT protein expressions. Interestingly, RuCO treatment resulted in opposite effects on wild-type and mutant p53 proteins. These results were similar to those of cells treated with geldanamycin (a heat shock protein (HSP)90 inhibitor), suggesting that RuCO might affect HSP90 activity. Moreover, RuCO induced mutant p53 protein destabilization accompanied by promotion of ubiquitination and proteasome degradation. The induction of HO-1 by cobalt protoporphyrin IX (CoPP) showed consistent results, while the addition of tin protoporphyrin IX (SnPP), an HO-1 enzymatic inhibitor, diminished the RuCO-mediated effect. RuCO induction of HO-1 expression was reduced by a p38 mitogen-activated protein kinase inhibitor (SB203580). Additionally, treatment with a chemopreventive compound, curcumin, induced HO-1 expression accompanied with reduction of HSP90 client protein expression. The induction of HO-1 by curcumin inhibited 12-O-tetradecanoyl-13-acetate (TPA)-elicited matrix metalloproteinase-9 expression and tumor invasion. In conclusion, we provide novel evidence underlying HO-1's antitumor mechanism. CO, a byproduct of HO-1, suppresses HSP90 protein activity, and the induction of HO-1 may possess potential as a cancer therapeutic.

Topics: Benzoquinones; Breast Neoplasms; Carbon Monoxide; Cell Line, Tumor; Cell Proliferation; Curcumin; Enzyme Induction; Female; Heme Oxygenase-1; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; MCF-7 Cells

The role of curcumin (diferuloylmethane), for cancer treatment has been an area of growing interest. However, due to its low absorption, the poor bioavailability of curcumin limits its clinical use. In this study, we reported an approach of encapsulation a curcumin by nanoliposome to achieve an improved bioavailability of a poorly absorbed hydrophobic compound. We demonstrated that liposomal preparations to deliver curcumin increase its bioavailability. Liposomes composed of salmon's lecithin also improved curcumin bioavailability compared to those constituted of rapeseed and soya lecithins. A real-time label-free cell analysis system based on real-time cell impedance monitoring was used to investigate the in vitro cytotoxicity of liposomal preparations.

Topics: Animals; Antineoplastic Agents; Biological Availability; Brassica rapa; Breast Neoplasms; Cell Proliferation; Curcumin; Female; Glycine max; Humans; Hydrophobic and Hydrophilic Interactions; Lecithins; Liposomes; MCF-7 Cells; Nanoparticles; Salmon

In developing countries, survival rates for breast cancer are poor and it accounts for 22.9% of all cancers in women. Curcumin, a major constituent from turmeric, is one of the well-known chemopreventive agents. Reports have shown that curcumin induces apoptosis in breast cancer cells. We synthesized an ortho-hydroxy substituted analog of curcumin (BDMC-A) and analyzed its cytotoxicity. The BDMC-A inhibited MCF-7 at a dose equivalent to that of curcumin (30 μM). The present study was aimed at delineating the apoptotic mechanism of BDMC-A in comparison to that of curcumin. In our study, BDMC-A exerted more potent effect on the modulation of selective apoptotic markers (intrinsic pathway: p53, Bcl-2, Bax, cyt c, Apaf-1, caspase-9, 3, PARP; extrinsic pathway: FasL, caspase 8) compared to curcumin. mRNA expression studies for Bcl2/Bax also supported the increased efficacy of BDMC-A. An in silico molecular docking study with PI3K revealed that the docking of BDMC-A was more potent compared to curcumin. Increased apoptotic induction by BDMC-A compared to curcumin was also demonstrated by Annexin V, Rh123 (ΔΨm), PI, Hoechst 33258, AO/EB fluorescent staining studies which showed characteristic apoptotic features like nuclear fragmentation and chromatin condensation. Moreover, BDMC-A treated cells effectively induced apoptosis through ROS intermediates compared to curcumin, as measured by 2'-7'-Dichlorodihydrofluorescein diacetate (DCFH-DA). Hence our overall results showed that BDMC-A induced apoptosis more effectively compared to curcumin and the activity can be attributed to the presence of hydroxyl group in the ortho position in its structure. Further researches are going on to delineate its molecular targets to evaluate its effect as a potent anticancer agent.

Topics: Antineoplastic Agents; Apoptosis; Blotting, Western; Breast Neoplasms; Curcumin; Dose-Response Relationship, Drug; Female; Humans; MCF-7 Cells; Molecular Docking Simulation; Molecular Structure; Real-Time Polymerase Chain Reaction

Cancer stem-like cells (CSC) and circulating tumor cells (CTC) have related properties associated with distant metastasis, but the mechanisms through which CSCs promote metastasis are unclear. In this study, we report that breast cancer cell lines with more stem-like properties display higher levels of microtentacles (McTN), a type of tubulin-based protrusion of the plasma cell membrane that forms on detached or suspended cells and aid in cell reattachment. We hypothesized that CSCs with large numbers of McTNs would more efficiently attach to distant tissues, promoting metastatic efficiency. The naturally occurring stem-like subpopulation of the human mammary epithelial (HMLE) cell line presents increased McTNs compared with its isogenic non-stem-like subpopulation. This increase was supported by elevated α-tubulin detyrosination and vimentin protein levels and organization. Increased McTNs in stem-like HMLEs promoted a faster initial reattachment of suspended cells that was inhibited by the tubulin-directed drug, colchicine, confirming a functional role for McTNs in stem cell reattachment. Moreover, live-cell confocal microscopy showed that McTNs persist in breast stem cell mammospheres as flexible, motile protrusions on the surface of the mammosphere. Although exposed to the environment, they also function as extensions between adjacent cells along cell-cell junctions. We found that treatment with the breast CSC-targeting compound curcumin rapidly extinguished McTN in breast CSC, preventing reattachment from suspension. Together, our results support a model in which breast CSCs with cytoskeletal alterations that promote McTNs can mediate attachment and metastasis but might be targeted by curcumin as an antimetastatic strategy.

Topics: Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cell Adhesion; Curcumin; Cytoskeleton; Female; Humans; Mammary Glands, Human; Molecular Targeted Therapy; Neoplastic Stem Cells; Pseudopodia; Spheroids, Cellular; Tubulin; Tumor Cells, Cultured

Leptin and its receptor are involved in breast carcinogenesis as mitogenic factors. Therefore, they could be considered as targets for breast cancer therapy. Expression of the leptin receptor gene could be modulated by leptin secretion. Silibinin and curcumin are herbal compounds with anti-cancer activity against breast cancer. The aim of this study was to assess their potential to inhibit of expression of the leptin gene and its receptor and leptin secretion. Cytotoxic effects of the two agents on combination on T47D breast cancer cells was investigated by MTT assay test after 24h treatment. With different concentrations the levels of leptin, leptin receptor genes expression were measured by reverse-transcription real-time PCR. Amount of secreted leptin in the culture medium was determined by ELISA. Data were statistically analyzed by one-way ANOVA test. The silibinin and curcumin combination inhibited growth of T47D cells in a dose dependent manner. There were also significant difference between control and treated cells in leptin expression and the quantity of secreted leptin with a relative decrease in leptin receptor expression. In conclusion, these herbal compounds inhibit the expression and secretion of leptin and it could probably be used as drug candidates for breast cancer therapy through leptin targeting in the future.

Topics: Antineoplastic Agents; Antioxidants; Breast Neoplasms; Cell Proliferation; Curcumin; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression Regulation, Neoplastic; Humans; Leptin; Real-Time Polymerase Chain Reaction; Receptors, Leptin; Signal Transduction; Silybin; Silymarin

Chronic inflammation is a major risk factor for the development and metastatic progression of cancer. We have previously reported that the chemopreventive polyphenol Curcumin inhibits the expression of the proinflammatory cytokines CXCL1 and -2 leading to diminished formation of breast and prostate cancer metastases. In the present study, we have analyzed the effects of Curcumin on miRNA expression and its correlation to the anti-tumorigenic properties of this natural occurring polyphenol. Using microarray miRNA expression analyses, we show here that Curcumin modulates the expression of a series of miRNAs, including miR181b, in metastatic breast cancer cells. Interestingly, we found that miR181b down-modulates CXCL1 and -2 through a direct binding to their 3'-UTR. Overexpression or inhibition of miR181b in metastatic breast cancer cells has a significant impact on CXCL1 and -2 and is required for the effect of Curcumin on these two cytokines. miR181b also mediates the effects of Curcumin on inhibition of proliferation and invasion as well as induction of apoptosis. Importantly, over-expression of miR181b in metastatic breast cancer cells inhibits metastasis formation in vivo in immunodeficient mice. Finally, we demonstrated that Curcumin up-regulates miR181b and down-regulates CXCL1 and -2 in cells isolated from several primary human breast cancers. Taken together, these data show that Curcumin provides a simple bridge to bring metastamir modulation into the clinic, placing it in a primary and tertiary preventive, as well as a therapeutic, setting.

Topics: Aged; Animals; Antineoplastic Agents; Breast; Breast Neoplasms; Cell Line, Tumor; Chemokine CXCL1; Chemokine CXCL2; Curcumin; Down-Regulation; Female; Humans; Mice; MicroRNAs; Middle Aged; Neoplasm Metastasis; Tumor Cells, Cultured; Up-Regulation

Curcumin can inhibit cell proliferation of breast cancer, but the mechanism for this inhibition remains unclear. Over-expression of Flap endonuclease 1 (Fen1), a DNA repair-specific nuclease, is involved in the development of breast cancer. Nrf2 is a master regulator of cellular antioxidant defense systems. Curcumin can induce the expression of Nrf2 in both non-breast cancer cells and breast cancer cells. However, whether curcumin-induced inhibition of breast cancer cell proliferation may involve Nrf2-mediated Fen1 expression is not yet understood. In this study, we demonstrated that curcumin inhibited Fen1-dependent proliferation of MCF-7 cells and significantly induced Nrf2 protein expression while inhibiting Fen1 protein expression. Curcumin could down-regulate Fen1 gene expression in a Nrf2-dependent manner. Further investigation revealed that curcumin could lead to Nrf2 translocation from the cytoplasm to the nucleus and decrease Fen1 promoter activity by decreasing the recruitment of Nrf2 to the Fen1 promoter. These data suggest that curcumin may inhibit the proliferation of breast cancer cells through Nrf2-mediated down-regulation of Fen1 expression, which may be a new mechanism of curcumin-induced tumor growth inhibition.

Topics: Antineoplastic Agents; Apoptosis; Blotting, Western; Breast Neoplasms; Cell Nucleus; Cell Proliferation; Chromatin Immunoprecipitation; Curcumin; Down-Regulation; Female; Flap Endonucleases; Gene Expression Regulation, Neoplastic; Humans; NF-E2-Related Factor 2; Promoter Regions, Genetic; Protein Transport; RNA, Small Interfering; Tumor Cells, Cultured

Curcumin (CUR) is a major naturally-occurring polyphenol of Curcuma species, which is commonly used as a yellow coloring and flavoring agent in foods. In recent years, it has been reported that CUR exhibits significant anti-tumor activity in vivo. However, the pharmacokinetic features of CUR have indicated poor oral bioavailability, which may be related to its extensive metabolism. The CUR metabolites might be responsible for the antitumor pharmacological effects in vivo. Tetrahydrocurcumin (THC) is one of the major metabolites of CUR. In the present study, we examined the efficacy and associated mechanism of action of THC in human breast cancer MCF-7 cells for the first time. Here, THC exhibited significant cell growth inhibition by inducing MCF-7 cells to undergo mitochondrial apoptosis and G2/M arrest. Moreover, co-treatment of MCF-7 cells with THC and p38 MAPK inhibitor, SB203580, effectively reversed the dissipation in mitochondrial membrane potential (Δψm), and blocked THC-mediated Bax up-regulation, Bcl-2 down-regulation, caspase-3 activation as well as p21 up-regulation, suggesting p38 MAPK might mediate THC-induced apoptosis and G2/M arrest. Taken together, these results indicate THC might be an active antitumor form of CUR in vivo, and it might be selected as a potentially effective agent for treatment of human breast cancer.

Topics: Apoptosis; Breast Neoplasms; Cell Division; Curcumin; Enzyme Activation; G2 Phase; Humans; MCF-7 Cells; p38 Mitogen-Activated Protein Kinases

Overexpression of oncoprotein Aurora-A increases drug resistance and promotes lung metastasis of breast cancer cells. Curcumin is an active anticancer compound in turmeric and curry. Here we observed that Aurora-A protein and kinase activity were reduced in curcumin-treated human breast chemoresistant nonmetastatic MCF-7 and highly metastatic cancer MDA-MB-231 cells. Curcumin acts in a similar manner to Aurora-A small interfering RNA (siRNA), resulting in monopolar spindle formation, S and G2/M arrest, and cell division reduction. Ectopic Aurora-A extinguished the curcumin effects. The anticancer effects of curcumin were enhanced by Aurora-A siRNA and produced additivity and synergism effects in cell division and monopolar phenotype, respectively. Combination treatment with curcumin overrode the chemoresistance to four Food and Drug Administration (FDA)-approved anticancer drugs (ixabepilone, cisplatin, vinorelbine, or everolimus) in MDA-MB-231 cells, which was characterized by a decrease in cell viability and the occurrence of an additivity or synergy effect. Ectopic expression of Aurora-A attenuated curcumin-enhanced chemosensitivity to these four tested drugs. A similar benefit of curcumin was observed in MCF-7 cells treated with ixabepilone, the primary systemic therapy to patients with invasive breast cancer (stages IIA-IIIB) before surgery. Antagonism effect was observed when MCF-7 cells were treated with curcumin plus cisplatin, vinorelbine or everolimus. Curcumin-induced enhancement in chemosensitivity was paralleled by significant increases (additivity or synergy effect) in apoptosis and cell cycle arrest at S and G2/M phases, the consequences of Aurora-A inhibition. These results suggest that a combination of curcumin with FDA-approved anticancer drugs warrants further assessment with a view to developing a novel clinical treatment for breast cancer.

Topics: Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Apoptosis; Aurora Kinase A; Breast Neoplasms; Cell Cycle Checkpoints; Cell Line, Tumor; Curcumin; Drug Resistance, Neoplasm; Female; Humans; MCF-7 Cells; Mitosis; RNA, Small Interfering

Although curcumin suppresses the growth of a variety of cancer cells, its poor absorption and low systemic bioavailability have limited its translation into clinics as an anticancer agent. In this study, we show that dimethoxycurcumin (DMC), a methylated, more stable analog of curcumin, is significantly more potent than curcumin in inducing cell death and reducing the clonogenicity of malignant breast cancer cells. Furthermore, DMC reduces the tumor growth of xenografted MDA-MB 435S cells more strongly than curcumin. We found that DMC induces paraptosis accompanied by excessive dilation of mitochondria and the endoplasmic reticulum (ER); this is similar to curcumin, but a much lower concentration of DMC is required to induce this process. DMC inhibits the proteasomal activity more strongly than curcumin, possibly causing severe ER stress and contributing to the observed dilation. DMC treatment upregulates the protein levels of CCAAT-enhancer-binding protein homologous protein (CHOP) and Noxa, and the small interfering RNA-mediated suppression of CHOP, but not Noxa, markedly attenuates DMC-induced ER dilation and cell death. Interestingly, DMC does not affect the viability, proteasomal activity or CHOP protein levels of human mammary epithelial cells, suggesting that DMC effectively induces paraptosis selectively in breast cancer cells, while sparing normal cells. Taken together, these results suggest that DMC triggers a stronger proteasome inhibition and higher induction of CHOP compared with curcumin, giving it more potent anticancer effects on malignant breast cancer cells.

Topics: Animals; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Proliferation; Cell Survival; Curcumin; Dose-Response Relationship, Drug; Female; Humans; Male; MCF-7 Cells; Mice; Mice, Inbred BALB C; Mice, Nude; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Proto-Oncogene Proteins c-bcl-2; RNA Interference; Time Factors; Transcription Factor CHOP; Transfection; Tumor Burden; Up-Regulation; Xenograft Model Antitumor Assays

Use of single chemotherapy agents has shown some limitations in anti-tumor treatment, such as development of drug resistance, severe adverse reactions and limited regime for therapeutic use. Combination of two or more therapeutic drugs is a feasible strategy to overcome these limitations. This paper reports study of co-delivery by core-shell nanoparticles (NPs) with hydrophobic PLLA core loaded with curcumin (Cur) and hydrophilic heparin shell adsorbing Doxorubicin (DOX). Characterizations of Cur-PEA NPs, Cur-PEA/heparin NPs and DOX adsorbing into Cur-PEA/heparin NPs (DOX-Cur NPs) were also investigated by transmission electron microscope (TEM) and Malvern Zetasizer. Studies on cellular uptake of DOX-Cur NPs demonstrated that both drugs were effectively taken up by 4T1 tumor cells. Furthermore, DOX-Cur NPs suppressed 4T1 tumor cells growth more efficiently than either DOX or Cur alone at the same concentrations, as measured by flow cytometry (FCM). We found out that intravenous injection of DOX-Cur NPs efficiently inhibited growth of subcutaneous 4T1 breast carcinoma in vivo (p < 0.01) and prolonged survival of the treated 4T1 breast carcinoma mice. Moreover, the pathological damage to the cardiac tissue in mice treated with DOX-Cur NPs was significantly less severe than that of mice treated with free DOX. This study suggested that DOX-Cur NPs may have promising applications in breast carcinoma therapy.

Topics: Animals; Breast Neoplasms; Cations; Cell Death; Cell Line, Tumor; Curcumin; Disease Models, Animal; Doxorubicin; Drug Carriers; Drug Delivery Systems; Endocytosis; Female; Flow Cytometry; Fluorescence; Heparin; Humans; Magnetic Resonance Spectroscopy; Mice; Mice, Inbred BALB C; Myocardium; Nanoparticles; Polyesters; Polyethyleneimine; Tissue Distribution

Breast cancer is the most common cancer in women. Bisphenol A (BPA), as a known endocrine disrupter, is closely related to the development of breast cancer. Curcumin has been clinically used in chemopreventation and treatment of cancer; however, it remains unknown whether microRNAs are involved in curcumin-mediated protection from BPA-associated promotive effects on breast cancer. In the present study, we showed that BPA exhibited estrogenic activity by increasing the proliferation of estrogen-receptor-positive MCF-7 human breast cancer cells and triggering transition of the cells from G1 to S phase. Curcumin inhibited the proliferative effects of BPA on MCF-7 cells. Meanwhile, BPA-induced upregulation of oncogenic miR-19a and miR-19b, and the dysregulated expression of miR-19-related downstream proteins, including PTEN, p-AKT, p-MDM2, p53, and proliferating cell nuclear antigen, were reversed by curcumin. Furthermore, the important role of miR-19 in BPA-mediated MCF-7 cell proliferation was also illustrated. These results suggest for the first time that curcumin modulates miR-19/PTEN/AKT/p53 axis to exhibit its protective effects against BPA-associated breast cancer promotion. Findings from this study could provide new insights into the molecular mechanisms by which BPA exerts its breast-cancer-promoting effect as well as its target intervention.

Topics: Benzhydryl Compounds; Breast Neoplasms; Cell Cycle; Cell Proliferation; Curcumin; Female; Humans; MCF-7 Cells; MicroRNAs; Phenols; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Signal Transduction; Tumor Suppressor Protein p53

Drug-eluting medical implants are more common, particularly for fighting against cancers. FDA and other drug regulatory bodies have approved many nanoformulated devices eluting active pharmaceutical ingredients and thus there is growing demand for further value- added devices. Nanofibre membranes are known for its versatility of drug incorporation and sustained drug release. We intend to fabricate natural ingredient or extract, and their combination loaded polycaprolactone (PCL) nanofibre for usage as drug-eluting stents or implants for anticancer activity against lung and breast cancers. The fabricated nanofibre membranes were characterised by scanning electron microscope for morphology, FT-IR for chemical nature and tensile testing for mechanical strengths. Release of curcumin was studied with time to find the applicability of the device as drug-eluting implant. The activity of the nanofibre membranes was tested against human breast cancer (MCF7) and lung cancer (A459) cell lines in vitro. In both the cell lines tested, 1% aloe vera and 5% curcumin-loaded PCL nanofibre exhibited 15% more cytotoxicity in comparison with the commercial drug 1% cis-Platin-loaded PCL nanofibre after 24 h incubation.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Curcumin; Drug Carriers; Humans; Lung Neoplasms; Nanofibers; Plant Extracts; Polyesters

Among polymeric nanoparticles designed for cancer therapy, PLGA nanoparticles have become one of the most popular polymeric devices for chemotherapeutic-based nanoformulations against several kinds of malignant diseases. Promising properties, including long-circulation time, enhanced tumor localization, interference with "multidrug" resistance effects, and environmental biodegradability, often result in an improvement of the drug bioavailability and effectiveness. In the present work, we have synthesized 1,7-bis(3,4-dimethoxyphenyl)-5-hydroxyhepta-1,4,6-trien-3-one (ASC-J9) and developed uniform ASC-J9-loaded PLGA nanoparticles of about 120 nm, which have been prepared by a single-emulsion process. Structural and morphological features of the nanoformulation were analyzed, followed by an accurate evaluation of the in vitro drug release kinetics, which exhibited Fickian law diffusion over 10 days. The intracellular degradation of ASC-J9-bearing nanoparticles within estrogen-dependent MCF-7 breast cancer cells was correlated to a time- and dose-dependent activity of the released drug. A cellular growth inhibition associated with a specific cell cycle G2/M blocking effect caused by ASC-J9 release inside the cytosol allowed us to put forward a hypothesis on the action mechanism of this nanosystem, which led to the final cell apoptosis. Our study was accomplished using Annexin V-based cell death analysis, MTT assessment of proliferation, radical scavenging activity, and intracellular ROS evaluation. Moreover, the intracellular localization of nanoformulated ASC-J9 was confirmed by a Raman optical imaging experiment designed ad hoc. PLGA nanoparticles and ASC-J9 proved also to be safe for a healthy embryo fibroblast cell line (3T3-L1), suggesting a possible clinical translation of this potential nanochemotherapeutic to expand the inherently poor bioavailability of hydrophobic ASC-J9 that could be proposed for the treatment of malignant breast cancer.

Topics: 3T3-L1 Cells; Animals; Apoptosis; Biocompatible Materials; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; Dose-Response Relationship, Drug; Drug Delivery Systems; Estrogens; Female; Free Radical Scavengers; Humans; Lactic Acid; MCF-7 Cells; Mice; Nanomedicine; Nanoparticles; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Reactive Oxygen Species; Spectrophotometry, Ultraviolet; Spectrum Analysis, Raman; Time Factors

In this research, we have synthesized guanidine functionalized PEGylated mesoporous silica nanoparticles as a novel and efficient drug delivery system (DDS). For this purpose, guanidine functionalized PEGylated I3ad mesoporous silica nanoparticle KIT-6 [Gu@PEGylated KIT-6] was utilized as a promising system for the effective delivery of curcumin into the breast cancer cells. The modified mesoporous silica nanoparticles (MSNs) was fully characterized by different techniques such as transmission and scanning electron microscopy (TEM & SEM), N2 adsorption-desorption measurement, thermal gravimetric analysis (TGA), X-ray powder diffraction (XRD), and dynamic light scattering (DLS). The average particle size of [Gu@PEGylated KIT-6] and curcumin loaded [Gu@PEGylated KIT-6] nanoparticles were about 60 and 70 nm, respectively. This new system exhibited high drug loading capacity, sustained drug release profile, and high and long term anticancer efficacy in human cancer cell lines. It showed pH-responsive controlled characteristics and highly programmed release of curcumin leading to the satisfactory results in in vitro breast cancer therapy. Our results depicted that the pure nanoparticles have no cytotoxicity against human breast adenocarcinoma cells (MCF-7), mouse breast cancer cells (4T1), and human mammary epithelial cells (MCF10A).

Topics: Animals; Apoptosis; Biological Transport; Breast Neoplasms; Curcumin; Drug Carriers; Guanidine; Humans; MCF-7 Cells; Mice; Models, Molecular; Molecular Conformation; Nanoparticles; Polyethylene Glycols; Porosity; Silicon Dioxide

Curcumin has shown therapeutic and/or adjuvant therapeutic effects on the treatment of some patients with breast cancer. However, its mechanisms of action are largely unknown. This study was designed to investigate its antitumor effect and underlying mechanisms in human breast cancer MDA-MB-231 and MCF-7 cells. The MTT assay was used to evaluate cell viability, and flow cytometry, acridine orange staining and transmission electron microscopy were used to detect apoptosis for cultured cells. The protein expression in cells was evaluated by western blot analysis. Breast tumors were established by subcutaneous injection of MDA-MB-231 cells in nude BALB/c mice, and curcumin was administered to the mice. The size of tumors was monitored and the weight of tumors was examined. The exposure of breast cancer cells to curcumin resulted in growth inhibition and the induction of apoptosis in a dose-dependent manner. We also found that the expression of Bcl-2 protein decreased and the expression of Bax protein increased which lead to an increase of the Bax/Bcl-2 ratio. In mice bearing MDA-MB-231 xenograft tumors, administration of curcumin showed a significant decrease of tumor volumes and tumor weight compared with the control. Our results showed that curcumin exhibited antitumor effects in breast cancer cells with an induction of apoptosis.

Topics: Animals; Antineoplastic Agents; Apoptosis; Blotting, Western; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; Female; Flow Cytometry; Humans; In Vitro Techniques; Mice; Mice, Inbred BALB C; Mice, Nude; Microscopy, Electron, Transmission; Xenograft Model Antitumor Assays

To explore the possible mechanism of curcumin in inducing the apoptosis of breast cancer cell MDA-MB-231.. Curcumin of different concentrations at 0, 10 25, 50, 100, 150, 200 micromol x L(-1) were used to intervene breast cancer cells MDA-MB-231 for 24 hours. MTT was used to observe its effect on the proliferation of breast cancer cells. The flow cytometry was used to detect its effect on the cell apoptosis. The real-time quantitative PCR and Western blot was used to assess the expression levels of GRP78 and CHOP in breast cancer cells.. Curcumin could inhibit the proliferative ability of breast cancer cells by inducing them in a concentration-dependent manner. Curcumin could significantly increase the expression levels of GRP78 and CHOP in breast cancer cells.. Curcumin could induce the apoptosis of breast cancer cells MDA-MB-231 by activating endoplasmic reticulum stress.

Topics: Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Curcumin; Drugs, Chinese Herbal; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Female; Heat-Shock Proteins; Humans; Transcription Factor CHOP

In order to explore the synergistic mechanisms of combinatorial treatment using curcumin and mitomycin C (MMC) for breast cancer, MCF-7 breast cancer xenografts were conducted to observe the synergistic effect of combinatorial treatment using curcumin and MMC at various dosages. The synergistic mechanisms of combinatorial treatment using curcumin and MMC on the inhibition of tumor growth were explored by differential gene expression profile, gene ontology (GO), ingenuity pathway analysis (IPA) and Signal-Net network analysis. The expression levels of selected genes identified by cDNA microarray expression profiling were validated by quantitative RT-PCR (qRT-PCR) and Western blot analysis. Effect of combinatorial treatment on the inhibition of cell growth was observed by MTT assay. Apoptosis was detected by flow cytometric analysis and Hoechst 33258 staining. The combinatorial treatment of 100 mg/kg curcumin and 1.5 mg/kg MMC revealed synergistic inhibition on tumor growth. Among 1501 differentially expressed genes, the expression of 25 genes exhibited an obvious change and a significant difference in 27 signal pathways was observed (p<0.05). In addition, Mapk1 (ERK) and Mapk14 (MAPK p38) had more cross-interactions with other genes and revealed an increase in expression by 8.14- and 11.84-fold, respectively during the combinatorial treatment by curcumin and MMC when compared with the control. Moreover, curcumin can synergistically improve tumoricidal effect of MMC in another human breast cancer MDA-MB-231 cells. Apoptosis was significantly induced by the combinatorial treatment (p<0.05) and significantly inhibited by ERK inhibitor (PD98059) in MCF-7 cells (p<0.05). The synergistic effect of combinatorial treatment by curcumin and MMC on the induction of apoptosis in breast cancer cells may be via the ERK pathway.

Topics: Animals; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Curcumin; Drug Synergism; Female; Flavonoids; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Humans; MCF-7 Cells; Mice; Mice, Nude; Mitomycin; Oligonucleotide Array Sequence Analysis; Signal Transduction; Transplantation, Heterologous

Drug resistance remains an on-going challenge in breast cancer chemotherapy. Combination of two or more drugs is an effective strategy to access context-specific multiple targets and overcome undesirable toxicity that is almost inevitable in single-drug chemotherapy. Many plant food-derived polyphenolic compounds have been proven to modulate many key factors responsible for cancer drug resistance, which makes them a promising group of low toxicity candidates for reversing cancer resistance. In this study, we analyzed the combination effect of two chemopreventive polyphenols, curcumin (Cur) and epigallocatechin-3-gallate (EGCG), in combating resistant breast cancer. Our present results showed that EGCG significantly enhanced the growth inhibition and apoptosis in both doxorubicin (DOX)-sensitive and resistant MCF-7 cells induced by Cur. The mechanism may be related to the further activation of caspase-dependent apoptotic signaling pathways and the enhanced cellular incorporation of Cur by inhibiting P-glycoprotein (P-gp) pump function. Moreover, Cur and EGCG in combination could enhance the toxicity of DOX and increase the intracellular level of DOX in resistant MCF-7 cells. Our findings with this practical combination of Cur and EGCG encourage us to move on to a promising strategy for successful treatment of human breast cancer resistance by combining two low-toxic chemotherapeutic agents from diet.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; ATP Binding Cassette Transporter, Subfamily B, Member 1; Breast Neoplasms; Caspases; Catechin; Cell Transformation, Neoplastic; Curcumin; Doxorubicin; Drug Combinations; Drug Resistance, Neoplasm; Drug Synergism; Female; Humans; MCF-7 Cells; Phytotherapy; Polyphenols; Signal Transduction

The existence of cancer stem cells (CSCs) has been associated with tumor initiation, therapy resistance, tumor relapse, angiogenesis, and metastasis. Curcumin, a plant ployphenol, has several anti-tumor effects and has been shown to target CSCs. Here, we aimed at evaluating (i) the mechanisms underlying the aggravated migration potential of breast CSCs (bCSCs) and (ii) the effects of curcumin in modulating the same.. The migratory behavior of MCF-7 bCSCs was assessed by using cell adhesion, spreading, transwell migration, and three-dimensional invasion assays. Stem cell characteristics were studied by using flow cytometry. The effects of curcumin on bCSCs were deciphered by cell viability assay, Western blotting, confocal microscopy, and small interfering RNA (siRNA)-mediated gene silencing. Evaluations of samples of patients with breast cancer were performed by using immunohistochemistry and flow cytometry.. Here, we report that bCSCs are endowed with aggravated migration property due to the inherent suppression of the tumor suppressor, E-cadherin, which is restored by curcumin. A search for the underlying mechanism revealed that, in bCSCs, higher nuclear translocation of beta-catenin (i) decreases E-cadherin/beta-catenin complex formation and membrane retention of beta-catenin, (ii) upregulates the expression of its epithelial-mesenchymal transition (EMT)-promoting target genes (including Slug), and thereby (iii) downregulates E-cadherin transcription to subsequently promote EMT and migration of these bCSCs. In contrast, curcumin inhibits beta-catenin nuclear translocation, thus impeding trans-activation of Slug. As a consequence, E-cadherin expression is restored, thereby increasing E-cadherin/beta-catenin complex formation and cytosolic retention of more beta-catenin to finally suppress EMT and migration of bCSCs.. Cumulatively, our findings disclose that curcumin inhibits bCSC migration by amplifying E-cadherin/beta-catenin negative feedback loop.

Topics: beta Catenin; Breast Neoplasms; Cadherins; Cell Line, Tumor; Cell Movement; Cell Survival; Curcumin; Feedback, Physiological; Female; Humans; MCF-7 Cells; Neoplastic Stem Cells

Curcuma zedoaria also known as Temu putih is traditionally used in food preparations and treatment of various ailments including cancer. The cytotoxic activity of hexane, dichloromethane, ethyl acetate, methanol, and the methanol-soxhlet extracts of Curcuma zedoaria rhizomes was tested on two human cancer cell lines (Ca Ski and MCF-7) and a noncancer cell line (HUVEC) using MTT assay. Investigation on the chemical components in the hexane and dichloromethane fractions gave 19 compounds, namely, labda-8(17),12 diene-15,16 dial (1), dehydrocurdione (2), curcumenone (3), comosone II (4), curcumenol (5), procurcumenol (6), germacrone (7), zerumbone epoxide (8), zederone (9), 9-isopropylidene-2,6-dimethyl-11-oxatricyclo[6.2.1.0(1,5)]undec-6-en-8-ol (10), furanodiene (11), germacrone-4,5-epoxide (12), calcaratarin A (13), isoprocurcumenol (14), germacrone-1,10-epoxide (15), zerumin A (16), curcumanolide A (17), curcuzedoalide (18), and gweicurculactone (19). Compounds (1-19) were evaluated for their antiproliferative effect using MTT assay against four cancer cell lines (Ca Ski, MCF-7, PC-3, and HT-29). Curcumenone (3) and curcumenol (5) displayed strong antiproliferative activity (IC50 = 8.3 ± 1.0 and 9.3 ± 0.3 μg/mL, resp.) and were found to induce apoptotic cell death on MCF-7 cells using phase contrast and Hoechst 33342/PI double-staining assay. Thus, the present study provides basis for the ethnomedical application of Curcuma zedoaria in the treatment of breast cancer.

Topics: Analysis of Variance; Breast Neoplasms; Cell Proliferation; Chromatography, Thin Layer; Curcuma; Female; Human Umbilical Vein Endothelial Cells; Humans; Indonesia; Malaysia; MCF-7 Cells; Microscopy, Fluorescence; Molecular Structure; Phytotherapy; Plant Extracts; Rhizome; Tetrazolium Salts; Thiazoles

5-Fluorouracil (5-FU) is the first rationally designed antimetabolite, which achieves its therapeutic efficacy through inhibition of the enzyme thymidylate synthase (TS), which is essential for the synthesis and repair of DNA. However, prolonged exposure to 5-FU induces TS overexpression, which leads to 5-FU resistance in cancer cells. Several studies have identified curcumin as a potent chemosensitizer against chemoresistance induced by various chemotherapeutic drugs. In this study, we report for the first time, with mechanism-based evidences, that curcumin can effectively chemosensitize breast cancer cells to 5-FU, thereby reducing the toxicity and drug resistance. We found that 10 μM 5-FU and 10 μM curcumin induces a synergistic cytotoxic effect in different breast cancer cells, independent of their receptor status, through the enhancement of apoptosis. Curcumin was found to sensitize the breast cancer cells to 5-FU through TS-dependent downregulation of nuclear factor-κB (NF-κB), and this observation was confirmed by silencing TS and inactivating NF-κB, both of which reduced the chemosensitizing efficacy of curcumin. Silencing of TS suppressed 5-FU-induced NF-κB activation, whereas inactivation of NF-κB did not affect 5-FU-induced TS upregulation, confirming that TS is upstream of NF-κB and regulates the activation of NF-κB in 5-FU-induced signaling pathway. Although Akt/PI3kinase and mitogen-activated protein kinase pathways are activated by 5-FU and downregulated by curcumin, they do not have any role in regulating the synergism. As curcumin is a pharmacologically safe and cost-effective compound, its use in combination with 5-FU may improve the therapeutic index of 5-FU, if corroborated by in vivo studies and clinical trials.

Topics: Annexin A5; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Caspases; Cell Line, Tumor; Curcumin; DNA Fragmentation; Down-Regulation; Drug Resistance, Neoplasm; Drug Synergism; Female; Fluorouracil; Humans; MCF-7 Cells; Mitogen-Activated Protein Kinases; NF-kappa B; Poly(ADP-ribose) Polymerases; Proto-Oncogene Proteins c-akt; RNA Interference; RNA, Small Interfering; Signal Transduction; Thymidylate Synthase; Up-Regulation

While the chemotherapeutic effect of curcumin, one of three major curcuminoids derived from turmeric, has been reported, largely unexplored are the effects of complex turmeric extracts more analogous to traditional medicinal preparations, as well as the relative importance of the three curcuminoids and their metabolites as anti-cancer agents. These studies document the pharmacodynamic effects of chemically-complex turmeric extracts relative to curcuminoids on human breast cancer cell growth and tumor cell secretion of parathyroid hormone-related protein (PTHrP), an important driver of cancer bone metastasis. Finally, relative effects of structurallyrelated metabolites of curcuminoids were assessed on the same endpoints. We report that 3 curcuminoid-containing turmeric extracts differing with respect to the inclusion of additional naturally occurring chemicals (essential oils and/or polar compounds) were equipotent in inhibiting human breast cancer MDA-MB-231 cell growth (IC50=10-16µg/mL) and secretion of osteolytic PTHrP (IC50=2-3µg/mL) when concentrations were normalized to curcuminoid content. Moreover, these effects were curcuminoid-specific, as botanically-related gingerol containing extracts had no effect. While curcumin and bis-demethoxycurcumin were equipotent to each other and to the naturally occurring curcuminoid mixture (IC50=58µM), demethoxycurcumin did not have any effect on cell growth. However, each of the individual curcuminoids inhibited PTHrP secretion (IC50=22-31µM) to the same degree as the curcuminoid mixture (IC50=16µM). Degradative curcuminoid metabolites (vanillin and ferulic acid) did not inhibit cell growth or PTHrP, while reduced metabolites (tetrahydrocurcuminoids) had inhibitory effects on cell growth and PTHrP secretion but only at concentrations ≥10-fold higher than the curcuminoids. These studies emphasize the structural and biological importance of curcuminoids in the anti-breast cancer effects of turmeric and contradict recent assertions that certain of the curcuminoid metabolites studied here mediate these anti-cancer effects.

Topics: Anticarcinogenic Agents; Breast Neoplasms; Cell Culture Techniques; Cell Line, Tumor; Cell Survival; Curcuma; Curcumin; Diarylheptanoids; Dose-Response Relationship, Drug; Female; Humans; Parathyroid Hormone-Related Protein; Plant Extracts; Rhizome; Zingiber officinale

Heterogeneously distributed hypoxic areas are a characteristic property of locally advanced breast cancers (BCa) and generally associated with therapeutic resistance, metastases, and poor patient survival. About 50% of locally advanced BCa, where radiotherapy is less effective are suggested to be due to hypoxic regions. In this study, we investigated the potential of bioactive phytochemicals in radio-sensitizing hypoxic BCa cells.. Hypoxic (O2-2.5%; N2-92.5%; CO2-5%) MCF-7 cells were exposed to 4 Gy radiation (IR) alone or after pretreatment with Curcumin (CUR), curcumin analog EF24, neem leaf extract (NLE), Genistein (GEN), Resveratrol (RES) or raspberry extract (RSE). The cells were examined for inhibition of NFκB activity, transcriptional modulation of 88 NFκB signaling pathway genes, activation and cellular localization of radio-responsive NFκB related mediators, eNos, Erk1/2, SOD2, Akt1/2/3, p50, p65, pIκBα, TNFα, Birc-1, -2, -5 and associated induction of cell death.. EMSA revealed that cells exposed to phytochemicals showed complete suppression of IR-induced NFκB. Relatively, cells exposed EF24 revealed a robust inhibition of IR-induced NFκB. QPCR profiling showed induced expression of 53 NFκB signaling pathway genes after IR. Conversely, 53, 50, 53, 53, 53 and 53 of IR-induced genes were inhibited with EF24, NLE, CUR, GEN, RES and RSE respectively. In addition, 25, 29, 24, 16, 11 and 21 of 35 IR-suppressed genes were further inhibited with EF24, NLE, CUR, GEN, RES and RSE respectively. Immunoblotting revealed a significant attenuating effect of IR-modulated radio-responsive eNos, Erk1/2, SOD2, Akt1/2/3, p50, p65, pIκBα, TNFα, Birc-1, -2 and -5 with EF24, NLE, CUR, GEN, RES or RSE. Annexin V-FITC staining showed a consistent and significant induction of IR-induced cell death with these phytochemicals. Notably, EF24 robustly conferred IR-induced cell death.. Together, these data identifies the potential hypoxic cell radio-sensitizers and further implies that the induced radio-sensitization may be exerted by selectively targeting IR-induced NFκB signaling.

Topics: Apoptosis; Blotting, Western; Breast Neoplasms; Cell Hypoxia; Cell Proliferation; Curcumin; Electrophoretic Mobility Shift Assay; Female; Flow Cytometry; Gamma Rays; Humans; Radiation-Sensitizing Agents; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Transcription Factor RelA; Tumor Cells, Cultured

Curcumin (CUR) has deserved extensive research due to its anti-inflammatory properties, of interest in human diseases including cancer. However, pleiotropic even paradoxical responses of tumor cells have been reported, and the mechanisms of action of CUR remain uncompletely elucidated.. (1)H-NMR spectroscopy-based metabolomics was applied to get novel insight into responses of MCF7 and MDA-MB-231 breast cancer cells to CUR alone, and MCF7 cells to CUR in cotreatment with docetaxel (DTX). In both cell types, a major target of CUR was glutathione metabolism. Total glutathione (GSx) increased at low dose CUR (≤ 10 mg.l(-1)-28 µM-) (up to +121% in MCF7 cells, P<0.01, and +138% in MDA-MB-231 cells, P<0.01), but decreased at high dose (≥ 25 mg.l(-1) -70 µM-) (-49%, in MCF7 cells, P<0.02, and -56% in MDA-MB-231 cells, P<0.025). At high dose, in both cell types, GSx-related metabolites decreased, including homocystein, creatine and taurine (-60 to -80%, all, P<0.05). Together with glutathione-S-transferase actvity, data established that GSx biosynthesis was upregulated at low dose, and GSx consumption activated at high dose. Another major target, in both cell types, was lipid metabolism involving, at high doses, accumulation of polyunsaturated and total free fatty acids (between ×4.5 and ×11, P<0.025), and decrease of glycerophospho-ethanolamine and -choline (about -60%, P<0.025). Multivariate statistical analyses showed a metabolic transition, even a biphasic behavior of some metabolites including GSx, between low and high doses. In addition, CUR at 10 mg.l(-1) in cotreatment with DTX induced modifications in glutathione metabolism, lipid metabolism, and glucose utilization. Some of these changes were biphasic depending on the duration of exposure to CUR.. Metabolomics reveals major metabolic targets of CUR in breast cancer cells, and biphasic responses that challenge the widely accepted beneficial effects of the phytochemical.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Comet Assay; Curcumin; Docetaxel; Female; Glutathione; Glutathione Transferase; Humans; Inflammation; Magnetic Resonance Spectroscopy; MCF-7 Cells; Metabolomics; Multivariate Analysis; Oxidative Stress; Taxoids; Treatment Outcome

Activated cancer-associated fibroblasts (CAFs) or myofibroblasts not only facilitate tumor growth and spread but also affect tumor response to therapeutic agents. Therefore, it became clear that efficient therapeutic regimens should also take into account the presence of these supportive cells and inhibit their paracrine effects. To this end, we tested the effect of low concentrations of curcumin, a pharmacologically safe natural product, on patient-derived primary breast CAF cells. We have shown that curcumin treatment upregulates p16(INK4A) and other tumor suppressor proteins while inactivates the JAK2/STAT3 pathway. This reduced the level of alpha-smooth muscle actin (α-SMA) and the migration/invasion abilities of these cells. Furthermore, curcumin suppressed the expression/secretion of stromal cell-derived factor-1 (SDF-1), interleukin-6 (IL-6), matrix metalloproteinase-2 (MMP-2), MMP-9, and transforming growth factor-β, which impeded their paracrine procarcinogenic potential. Intriguingly, these effects were sustained even after curcumin withdrawal and cell splitting. Therefore, using different markers of senescence [senescence-associated β-galactosidase (SA-β-gal) activity, Ki-67 and Lamin B1 levels, and bromodeoxyuridine incorporation], we have shown that curcumin markedly suppresses Lamin B1 and triggers DNA damage-independent senescence in proliferating but not quiescent breast stromal fibroblasts. Importantly, this curcumin-related senescence was p16(INK4A)-dependent and occurred with no associated inflammatory secretory phenotype. These results indicate the possible inactivation of cancer-associated myofibroblasts and present the first indication that curcumin can trigger DNA damage-independent and safe senescence in stromal fibroblasts.

Topics: Actins; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cell Movement; Cellular Senescence; Curcumin; Cyclin-Dependent Kinase Inhibitor p16; DNA Damage; Dose-Response Relationship, Drug; Female; Fibroblasts; Gene Expression Regulation; Humans; Interleukin-6; Ki-67 Antigen; Lamin Type B; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; STAT3 Transcription Factor; Stromal Cells; Transforming Growth Factor beta; Tumor Cells, Cultured; Up-Regulation

Curcumin, a biphenyl compound derived from rhizome, is a powerful anti-cancer agent. Emodin is an active component isolated from the root and rhizome of Rheum palmatum that has been widely used in traditional Chinese medicine for the treatment of various diseases. Currently, there are no studies examining the effect of curcumin in combination with emodin on tumor cell growth. In this study, we report for the first time that combined curcumin and emodin administration synergistically inhibits proliferation (MTT assay), survival (flow cytometry), and invasion (transwell migration assay) of breast cancer cells. Synergism is determined by the Chou-Talalay method. Moreover, we demonstrate that miR-34a is upregulated by curcumin and emodin. This microRNA helps mediate the anti-tumor effects of curcumin and emodin by downregulating Bcl-2 and Bmi-1. Our results not only provide insight into the mechanism of synergy between curcumin and emodin in breast cancer cells, but also suggest a new and potentially useful approach for breast cancer therapy.

Topics: Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Curcumin; Drug Synergism; Emodin; Female; Gene Expression Regulation, Neoplastic; Humans; Inhibitory Concentration 50; MicroRNAs; Neoplasm Invasiveness; Polycomb Repressive Complex 1; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Up-Regulation

Tumor-associated macrophages (TAMs) are essential cellular components within tumor microenvironment (TME). TAMs are educated by TME to transform to M2 polarized population, showing a M2-like phenotype, IL-10(high), IL-12(low), TGF-β(high). STAT3 signaling triggers crosstalk between tumor cells and TAMs, and is crucial for the regulation of malignant progression. In our study, legumain-targeting liposomal nanoparticles (NPs) encapsulating HC were employed to suppress STAT3 activity and "re-educate" TAMs, and to investigate the effects of suppression of tumor progression in vivo. The results showed that TAMs treated by HC encapsuled NPs could switch to M1-like phenotype, IL-10(low), IL-12(high), TGF-β(low), and the "re-educated" macrophages (M1-like macrophages) considerably demonstrated opposite effect of M2-like macrophages, especially the induction of 4T1 cells migration and invasion in vitro, and suppression of tumor growth, angiogenesis and metastasis in vivo. These data indicated that inhibition of STAT3 activity of TAMs by HC-NPs was able to reverse their phenotype and could regulate their crosstalk between tumor cells and TAMs in order to suppress tumor progression.

Topics: Animals; Apoptosis; Blotting, Western; Breast Neoplasms; Cell Cycle; Cell Line; Cell Line, Tumor; Cell Survival; Curcumin; Female; Flow Cytometry; Hydrazines; Macrophages; Mice; Mice, Inbred BALB C; Nanoparticles; STAT3 Transcription Factor

The TNF-related apoptosis inducing ligand (TRAIL) has promising anti-cancer therapeutic activity, although significant percentage of primary tumors resistant to TRAIL-induced apoptosis remains an obstacle to the extensive use of TRAIL-based mono-therapies. Natural compound curcumin could potentially sensitize resistant cancer cells to TRAIL. We found that the combination of TRAIL with curcumin can synergistically induces apoptosis in three TRAIL-resistant breast cancer cell lines. The mechanism behind this synergistic cell death was investigated by examining an effect of curcumin on the expression and activation of TRAIL-associated cell death proteins. Immunoblotting, RNA interference, and use of chemical inhibitors of TRAIL-activate signaling revealed differential effects of curcumin on the expression of Mcl-1 and activities of ERK and Akt. Curcumin-induced production of reactive oxygen species did not affect total expression of DR5 but it enhanced mobilization of DR5 to the plasma membrane. In these breast cancer cells curcumin also induced downregulation of IAP proteins. Taken together, our data suggest that a combination of TRAIL and curcumin is a potentially promising treatment for breast cancer, although the specific mechanisms involved in this sensitization could differ even among breast cancer cells of different origins.

Topics: Apoptosis; Apoptosis Regulatory Proteins; Breast Neoplasms; Cell Line, Tumor; Cell Membrane; Curcumin; Down-Regulation; Drug Screening Assays, Antitumor; Drug Synergism; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Myeloid Cell Leukemia Sequence 1 Protein; Protein Transport; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Receptors, TNF-Related Apoptosis-Inducing Ligand; Signal Transduction; TNF-Related Apoptosis-Inducing Ligand

Telomerase has been considered as an attractive molecular target for breast cancer therapy. The main objective of this work is to assess the inhibitory effects of silibinin and curcumin, two herbal substances, on telomerase gene expression in breast cancer cells.. For determination of cell viability tetrazolium-based assays were conducted after 24, 48, and 72 h exposure times and expression of human telomerase reverse transcriptase gene was measured with real-time PCR.. Each compound exerted cytotoxic effects on T47D cells and inhibited telomerase gene expression, both in a time-and dose-dependent manner. The mixture of curcumin and silibinin showed relatively more inhibitory effect on growth of T47D cells and hTERT gene expression as compared with either agent alone.. These findings suggest that cell viability along with hTERT gene expression in breast cancer cells could be reduced by curcumin and silibinin.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Apoptosis; Breast Neoplasms; Cell Proliferation; Curcumin; Female; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Silybin; Silymarin; Telomerase; Tumor Cells, Cultured

More than 85% of breast cancers are sporadic and attributable to long-term exposure to environmental carcinogens and co-carcinogens. To identify co-carcinogens with abilities to induce cellular pre-malignancy, we studied the activity of triclocarban (TCC), an antimicrobial agent commonly used in household and personal care products. Here, we demonstrated, for the first time, that chronic exposure to TCC at physiologically-achievable nanomolar concentrations resulted in progressive carcinogenesis of human breast cells from non-cancerous to pre-malignant. Pre-malignant carcinogenesis was measured by increasingly-acquired cancer-associated properties of reduced dependence on growth factors, anchorage-independent growth and increased cell proliferation, without acquisition of cellular tumorigenicity. Long-term TCC exposure also induced constitutive activation of the Erk-Nox pathway and increases of reactive oxygen species (ROS) in cells. A single TCC exposure induced transient induction of the Erk-Nox pathway, ROS elevation, increased cell proliferation, and DNA damage in not only non-cancerous breast cells but also breast cancer cells. Using these constitutively- and transiently-induced changes as endpoints, we revealed that non-cytotoxic curcumin was effective in intervention of TCC-induced cellular pre-malignancy. Our results lead us to suggest that the co-carcinogenic potential of TCC should be seriously considered in epidemiological studies to reveal the significance of TCC in the development of sporadic breast cancer. Using TCC-induced transient and constitutive endpoints as targets will likely help identify non-cytotoxic preventive agents, such as curcumin, effective in suppressing TCC-induced cellular pre-malignancy.

Topics: Anti-Infective Agents; Antineoplastic Agents; Breast; Breast Neoplasms; Carbanilides; Carcinogens, Environmental; Cell Line; Cell Transformation, Neoplastic; Curcumin; DNA Damage; Female; Humans; MAP Kinase Signaling System; Reactive Oxygen Species

Natural compounds have been studied as a source of countless bioactive compounds with diverse activities. Among them, many dietary phytochemicals have been thoroughly studied for their cytotoxic or apoptotic effects in several cellular models in order to explain their anticancer capacity. Curcumin and resveratrol are two natural compounds with a large body of evidence showing their cytotoxic activity against a wide variety of cancer cells; however, their poor absorption, bioavailability, and low selectivity have limited their clinical use. With the aim of improving bioavailability and selectivity, the antiproliferative effects of free-, liposomed-, and immunoliposomed-curcumin and/or resveratrol formulations have been compared in two human breast cancer cell lines with different HER2 expression levels. The results demonstrate that when HER2-targeted immunoliposomes are coupled to trastuzumab there is a dramatic increase in the antiproliferative effects of curcumin and resveratrol in HER2 positive human breast cancer cells in comparison to regular liposomed or free forms, indicating an increase of its therapeutic effect. The enhancement of the cytotoxic effects was also correlated to the uptake of curcumin at intracellular level, as shown by using ImageStream technique. The striking efficacy of the immunoliposomed formulation containing both resveratrol and curcumin suggests a multitargeted mechanism of action that deserves further study. These findings show the potential of HER2-targeted nanovesicles to develop new drug delivery systems for cancer therapy based on these compounds and justify further preclinical trials.

Topics: Antibodies, Monoclonal, Humanized; Anticarcinogenic Agents; Antineoplastic Agents; Biological Availability; Biological Products; Breast Neoplasms; Carcinoma, Ductal, Breast; Cell Division; Cell Line, Tumor; Cholesterol; Chromatography, High Pressure Liquid; Curcumin; Drug Compounding; Drug Screening Assays, Antitumor; Female; Gene Expression Regulation, Neoplastic; Genes, erbB-2; Humans; Immunoconjugates; Liposomes; Neoplasm Proteins; Particle Size; Phosphatidylcholines; Phosphatidylethanolamines; Receptor, ErbB-2; Resveratrol; Stilbenes; Trastuzumab

Triple-negative breast cancer (TNBC) is defined by a lack of expression of the estrogen receptor (ER), progesterone receptor (PR), and epidermal growth factor receptor 2 (HER 2). Therefore, targeted therapy agents may not be used, and therapy is largely limited to chemotherapy. Doxorubicin treatment consequently acquires undesired malignance characteristics [i.e., epithelial-mesenchymal transition (EMT) and multi-drug resistance]. Our results illustrated that doxorubicin triggered EMT and resulted in the acquisition of a mesenchymal phenotype in TNBC cells. Moreover, we found that transforming growth factor-β (TGF-β) and PI3K/AKT signaling pathways were acquired for doxorubicin-induced EMT. Interestingly, we found that curcumin suppressed doxorubicin-induced EMT. Curcumin reversed doxorubicin-induced morphological changes, inhibited doxorubicin-induced downregulation of E-cadherin expressions, and inhibited doxorubicin-induced upregulation of vimentin expression. We also found that curcumin inhibited doxorubicin-induced EMT by inhibiting the TGF-β and PI3K/AKT signaling pathways. Moreover, curcumin enhanced the antiproliferative effects of doxorubicin in TNBC cells. In summary, our results suggest that doxorubicin in combination with curcumin may be a potential therapy for TNBC.

Topics: Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Curcumin; Down-Regulation; Doxorubicin; Epithelial-Mesenchymal Transition; Female; Humans; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Transforming Growth Factor beta

Despite numerous useful anticancer properties of curcumin, its utility is limited due to its hydrophobic structure. In this study, we investigated the comparative antiproliferative effect of PAMAM encapsulating curcumin with naked curcumin on the T47D breast cancer cell line.. Cytotoxic effects of PAMAM dendrimers encapsulating curcumin and curcumin alone were investigated by MTT assay. After treating cells with different concentrations of both curcumin alone and curcumin encapsulated for 24h, telomerase activity was determined by TRAP assay.. While PAMAM dendrimers encapsulating curcumin had no cytotoxicity on cancer cells, they decreased the IC50 for proliferation and also increased the inhibitory effect on telomerase activity.. Considering the non-toxicity in addition to effectiveness for enhancing curcumin anticancer properties, dendrimers could be considered good therapeutic vehicles for this hydrophobic agent.

Topics: Antineoplastic Agents; Biocompatible Materials; Breast Neoplasms; Cell Proliferation; Curcumin; Dendrimers; Female; Humans; Telomerase; Tumor Cells, Cultured

Breast cancer patients with HER-2 positive or estrogen receptor negative tumors have a poor prognosis because these tumors are aggressive and respond poorly to standard therapies. Histone deacetylase (HDAC) inhibitors have been shown to decreased cell survival, which suggests that HDAC inhibitors may be developed for preventing and treating breast cancer. Curcumin has anti-inflammatory and proapoptotic effects in cancer cells. We determined whether the HDAC inhibitor, Tricostatin A (TSA) in combination with curcumin would produce greater antiproliferative and apoptotic effects than either agent alone. Increasing the concentration of curcumin from 10 to 20 µM enhanced the growth inhibitory effects of the combination in SkBr3 and 435eB breast cancer cells, which was accompanied by decreased viability along with decreased phosphorylation of ERK and Akt. The decreased cell viability observed in SkBr3 cells when curcumin was combined with TSA led to a G0/G1 cell cycle arrest and increased p21 and p27, and decreased Cyclin D1 protein expression. The combination induced cleavage of caspase 3 and poly(ADP-ribose) polymerase-1, suggesting that cell death occurred by apoptosis. There were no changes in protein expression of Bcl2, Bax, or Bcl-xL and decreased expression of p53. The combination increased protein expression of phosphorylated JNK and phosphorylated p38. Pharmacological inhibition of JNK, but not p38, attenuated the decreased viability induced by the curcumin and TSA combination. We conclude that p53 independent apoptosis induced by combining curcumin and TSA involves JNK activation. These findings provide a rationale for exploring the potential benefits of the combination of curcumin with TSA for treatment of breast cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; bcl-2-Associated X Protein; bcl-X Protein; Breast Neoplasms; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Survival; Curcumin; Cyclin D1; Enzyme Inhibitors; Female; Humans; Hydroxamic Acids; Imidazoles; MAP Kinase Kinase 4; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Pyridines

Curcumin and methylseleninic acid (MSeA) are well-documented dietary chemopreventive agents. Apoptosis appears to be a major mechanism for both agents to exert anti-cancer activity. The purpose of the present study was designed to determine whether the apoptotic effect on human cancer cells can be enhanced by combining curcumin with MSeA. Apoptosis was evaluated by Annexin V staining of externalized phosphatidylserine by flow cytometry. Expression of protein was analyzed by Western blotting. Localization of apoptosis-inducing factor (AIF) was detected by immunocytochemistry. RNA interference was employed to inhibit expression of specific protein. We found here that combining curcumin with MSeA led to a significantly enhanced apoptosis in both MDA-MB-231 breast cancer cells and DU145 prostate cancer cells. Further mechanistic investigations revealed that curcumin treatment alone caused a concentration dependent upregulation of Mcl-1, which can be overcome by combining it with MSeA. In line with the Mcl-1 reduction, an enhanced mitochondrial permeability transition and AIF nuclear translocation by the combination were achieved. In addition, an increased suppression of focal adhesion kinase activity was observed in the combination-treated cells which were associated with cell detachment-induced apoptosis by the combination. Our findings suggest that curcumin/MSeA combination holds excellent potential for improving their efficacy against human breast and prostate cancer through enhanced apoptosis induction.

Topics: Active Transport, Cell Nucleus; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Apoptosis Inducing Factor; Breast Neoplasms; Cell Line, Tumor; Curcumin; Female; Focal Adhesion Kinase 1; Humans; Male; Myeloid Cell Leukemia Sequence 1 Protein; Organoselenium Compounds; Prostatic Neoplasms; Reactive Oxygen Species; Up-Regulation

Epithelial-mesenchymal transition (EMT) is considered a critical event in cancer cell invasion and metastasis. Emerging evidence has shown that curcumin may prevent or delay the progression of cancer, an effect that may be partially due to its ability to disrupt EMT, yet this has not yet been demonstrated. In this study, we used lipopolysaccharide (LPS) to trigger EMT in MCF-7 and MDA-MB-231 breast cancer cell lines and showed that curcumin inhibited LPS-induced morphological changes, decreased the expression of LPS-induced markers of EMT such as vimentin, and increased the expression of E-cadherin, resulting in the inhibition of in vitro cell motility and invasiveness. We discovered that these actions were mediated through the inactivation of NF-κB-Snail signaling pathways. Our results indicate that curcumin plays an important role in the inhibition of LPS-induced EMT in breast cancer cells through the downregulation of NF-κB-Snail activity. These data provide a new perspective of the anti-invasive mechanism of curcumin, indicating that the effect is partly due to its ability to attack the EMT process.

Topics: Antineoplastic Agents; Blotting, Western; Breast Neoplasms; Cell Adhesion; Cell Movement; Cell Proliferation; Curcumin; Down-Regulation; Epithelial-Mesenchymal Transition; Female; Humans; Lipopolysaccharides; NF-kappa B; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Snail Family Transcription Factors; Transcription Factors; Tumor Cells, Cultured

Effects of curcuminoids on breast cancer cell secretion of the bone-resorptive peptide parathyroid hormone-related protein (PTHrP) and on lytic breast cancer bone metastasis were evaluated. In vitro, transforming growth factor (TGF)-β-stimulated PTHrP secretion was inhibited by curcuminoids (IC50 = 24 μM) in MDA-MB-231 human breast cancer cells independent of effects on cell growth inhibition. Effects on TGF-β signaling revealed decreases in phospho-Smad2/3 and Ets-1 protein levels with no effect on p-38 MAPK-mediated TGF-β signaling. In vivo, mice were inoculated with MDA-MB-231 cells into the left cardiac ventricle and treated ip every other day with curcuminoids (25 or 50 mg/kg) for 21 days. Osteolytic bone lesion area was reduced up to 51% (p < 0.01). Consistent with specific effects on bone osteolysis, osteoclast number at the bone-tumor interface was reduced up to 53% (p < 0.05), while tumor area within bone was unaltered. In a separate study, tumor mass in orthotopic mammary xenografts was also unaltered by treatment. These data suggest that curcuminoids prevent TGF-β induction of PTHrP and reduce osteolytic bone destruction by blockade of Smad signaling in breast cancer cells.

Topics: Animals; Bone Neoplasms; Breast Neoplasms; Curcumin; Disease Models, Animal; Female; Humans; Mice; Molecular Structure; Osteolysis; Parathyroid Hormone-Related Protein; Signal Transduction; Transforming Growth Factor beta

Widespread distribution of bisphenol-A (BPA) complicates epidemiological studies of possible carcinogenic effects on the breast because there are few unexposed controls. To address this challenge, we previously developed non-cancerous human high-risk donor breast epithelial cell (HRBEC) cultures, wherein BPA exposure could be controlled experimentally. BPA consistently induced activation of the mammalian target of rapamycin (mTOR) pathway--accompanied by dose-dependent evasion of apoptosis and increased proliferation--in HRBECs from multiple donors. Here, we demonstrate key molecular changes underlying BPA-induced cellular reprogramming. In 3/3 BPA-exposed HRBEC cell lines, and in T47D breast cancer cells, proapoptotic negative regulators of the cell cycle (p53, p21(WAF1) and BAX) were markedly reduced, with concomitant increases in proliferation-initiating gene products (proliferating cell nuclear antigen, cyclins, CDKs and phosphorylated pRb). However, simultaneous exposure to BPA and the polyphenol, curcumin, partially or fully reduced the spectrum of effects associated with BPA alone, including mTOR pathway proteins (AKT1, RPS6, pRPS6 and 4EBP1). BPA exposure induced an increase in the ERα (Estrogen Receptor): ERβ ratio--an effect also reversed by curcumin (analysis of variance, P < 0.02 for all test proteins). At the functional level, concurrent curcumin exposure reduced BPA-induced apoptosis evasion and rapid growth kinetics in all cell lines to varying degrees. Moreover, BPA extended the proliferation potential of 6/6 primary finite-life HRBEC cultures--another effect reduced by curcumin. Even after removal of BPA, 1/6 samples maintained continuous growth--a hallmark of cancer. We show that BPA exposure induces aberrant expression of multiple checkpoints that regulate cell survival, proliferation and apoptosis and that such changes can be effectively ameliorated.

Topics: Apoptosis; Apoptosis Regulatory Proteins; Benzhydryl Compounds; Breast Neoplasms; Cell Cycle; Cell Cycle Proteins; Cell Proliferation; Cell Survival; Curcumin; Down-Regulation; Epithelial Cells; Estrogen Receptor alpha; Estrogens, Non-Steroidal; Female; Humans; Hydroxytestosterones; Kinetics; Mammary Glands, Human; Phenols; Primary Cell Culture; Signal Transduction; TOR Serine-Threonine Kinases; Tumor Suppressor Protein p53

Curcumin, a principal component of turmeric (Curcuma longa), has potential therapeutic activities against breast cancer through multiple signaling pathways. Increasing evidence indicates that curcumin reverses chemo-resistance and sensitizes cancer cells to chemotherapy and targeted therapy in breast cancer. To date, few studies have explored its potential antiproliferation effects and resistance reversal in antiestrogen-resistant breast cancer. In this study, we therefore investigated the efficacy of curcumin alone and in combination with tamoxifen in the established antiestrogen-resistant breast cancer cell lines MCF-7/LCC2 and MCF-7/LCC9. We discovered that curcumin treatment displayed anti-proliferative and pro-apoptotic activities and induced cell cycle arrest at G2/M phase. Of note, the combination of curcumin and tamoxifen resulted in a synergistic survival inhibition in MCF-7/LCC2 and MCF-7/LCC9 cells. Moreover, we found that curcumin targeted multiple signals involved in growth maintenance and resistance acquisition in endocrine resistant cells. In our cell models, curcumin could suppress expression of pro-growth and anti-apoptosis molecules, induce inactivation of NF-κB, Src and Akt/mTOR pathways and downregulate the key epigenetic modifier EZH2. The above findings suggested that curcumin alone and combinations of curcumin with endocrine therapy may be of therapeutic benefit for endocrine-resistant breast cancer.

Topics: Antineoplastic Agents, Hormonal; Apoptosis; Apoptosis Regulatory Proteins; Breast Neoplasms; Cell Proliferation; Cell Survival; Curcumin; Cyclin D1; Down-Regulation; Drug Resistance, Neoplasm; Drug Synergism; Extracellular Signal-Regulated MAP Kinases; Female; G2 Phase Cell Cycle Checkpoints; Gene Expression; Humans; MCF-7 Cells; NF-kappa B; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-myc; Signal Transduction; Tamoxifen; TOR Serine-Threonine Kinases

PLGA nanoparticles are among the most studied polymer nanoformulations for several drugs against different kinds of malignant diseases, thanks to their in vivo stability and tumor localization exploiting the well-documented "enhanced permeation and retention" (EPR) effect. In this paper, we have developed uniform curcumin-bearing PLGA nanoparticles by a single-emulsion process, which exhibited a curcumin release following a Fickian-law diffusion over 10 days in vitro. PLGA nanoparticles were about 120 nm in size, as determined by dynamic light scattering, with a surface negative charge of -30 mV. The loading ratio of encapsulated drug in our PLGA nanoformulation was 8 wt%. PLGA encapsulation provided efficient protection of curcumin from environment, as determined by fluorescence emission experiments. Next, we have investigated the possibility to study the intracellular degradation of nanoparticles associated with a specific G2/M blocking effect on MCF7 breast cancer cells caused by curcumin release in the cytoplasm, which provided direct evidence on the mechanism of action of our nanocomplex. This study was carried out using Annexin V-based cell death analysis, MTT assessment of proliferation, flow cytometry, and confocal laser scanning microscopy. PLGA nanoparticles proved to be completely safe, suggesting a potential utilization of this nanocomplex to improve the intrinsically poor bioavailability of curcumin for the treatment of severe malignant breast cancer.

Topics: Apoptosis; Biocompatible Materials; Biological Availability; Breast Neoplasms; Cell Cycle Checkpoints; Cell Proliferation; Curcumin; Cytoplasm; Drug Delivery Systems; Female; Humans; Lactic Acid; MCF-7 Cells; Microscopy, Confocal; Nanoparticles; Particle Size; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer

Post-translational modifications (PTMs) of histones and other proteins are perturbed in tumours. For example, reduced levels of acetylated H4K16 and trimethylated H4K20 are associated with high tumour grade and poor survival in breast cancer. Drug-like molecules that can reprogram selected histone PTMs in tumour cells are therefore of interest as potential cancer chemopreventive agents. In this study we assessed the effects of the phytocompounds garcinol and curcumin on histone and p53 modification in cancer cells, focussing on the breast tumour cell line MCF7.. Cell viability/proliferation assays, cell cycle analysis by flow cytometry, immunodetection of specific histone and p53 acetylation marks, western blotting, siRNA and RT-qPCR.. Although treatment with curcumin, garcinol or the garcinol derivative LTK-14 hampered MCF7 cell proliferation, differential effects of these compounds on histone modifications were observed. Garcinol treatment resulted in a strong reduction in H3K18 acetylation, which is required for S phase progression. Similar effects of garcinol on H3K18 acetylation were observed in the osteosarcoma cells lines U2OS and SaOS2. In contrast, global levels of acetylated H4K16 and trimethylated H4K20 in MCF7 cells were elevated after garcinol treatment. This was accompanied by upregulation of DNA damage signalling markers such as γH2A.X, H3K56Ac, p53 and TIP60. In contrast, exposure of MCF7 cells to curcumin resulted in increased global levels of acetylated H3K18 and H4K16, and was less effective in inducing DNA damage markers. In addition to its effects on histone modifications, garcinol was found to block CBP/p300-mediated acetylation of the C-terminal activation domain of p53, but resulted in enhanced acetylation of p53K120, and accumulation of p53 in the cytoplasmic compartment. Finally, we show that the elevation of H4K20Me3 levels by garcinol correlated with increased expression of SUV420H2, and was prevented by siRNA targeting of SUV420H2.. In summary, although garcinol and curcumin can both inhibit histone acetyltransferase activities, our results show that these compounds have differential effects on cancer cells in culture. Garcinol treatment alters expression of chromatin modifying enzymes in MCF7 cells, resulting in reprogramming of key histone and p53 PTMs and growth arrest, underscoring its potential as a cancer chemopreventive agent.

Topics: Acetylation; Antineoplastic Agents; Blotting, Western; Breast Neoplasms; Cell Cycle; Cell Proliferation; Cell Survival; CREB-Binding Protein; Curcumin; DNA Damage; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Flow Cytometry; Histone Acetyltransferases; Histone-Lysine N-Methyltransferase; Histones; Humans; Immunohistochemistry; Lysine Acetyltransferase 5; MCF-7 Cells; Methylation; Polymerase Chain Reaction; Protein Processing, Post-Translational; RNA Interference; Terpenes; Time Factors; Transfection; Tumor Suppressor Protein p53

The delivery of curcumin, a broad-spectrum anticancer drug, has been explored in the form of liposomal nanoparticles to treat osteosarcoma (OS). Curcumin is water insoluble and an effective delivery route is through encapsulation in cyclodextrins followed by a second encapsulation in liposomes. Liposomal curcumin's potential was evaluated against cancer models of mesenchymal (OS) and epithelial origin (breast cancer). The resulting 2-Hydroxypropyl-γ-cyclodextrin/curcumin - liposome complex shows promising anticancer potential both in vitro and in vivo against KHOS OS cell line and MCF-7 breast cancer cell line. An interesting aspect is that liposomal curcumin initiates the caspase cascade that leads to apoptotic cell death in vitro in comparison with DMSO-curcumin induced autophagic cell death. In addition, the efficiency of the liposomal curcumin formulation was confirmed in vivo using a xenograft OS model. Curcumin-loaded γ-cyclodextrin liposomes indicate significant potential as delivery vehicles for the treatment of cancers of different tissue origin.. Curcumin-loaded γ-cyclodextrin liposomes were demonstrated in vitro to have significant potential as delivery vehicles for the treatment of cancers of mesenchymal and epithelial origin. Differences between mechanisms of cell death were also evaluated.

Topics: Animals; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Caspases; Cell Line, Tumor; Curcumin; Female; gamma-Cyclodextrins; Humans; Liposomes; Mice; Mice, Nude; Neoplasm Proteins; Neoplasm Transplantation; Osteosarcoma; Transplantation, Heterologous; Xenograft Model Antitumor Assays

Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione), is extracted from the plant Curcuma longa. It was recently reported for its anticancer effect on several types of cancer cells in vitro however, the molecular mechanisms of this anticancer effect are not fully understood. In the present study, we evaluated the effects of curcumin on human mammary epithelial carcinoma MCF-7 cells. Cells were treated with curcumin and examined for cell viability by MTT assay. The cells invasion was demonstrated by transwell assay. The binding activity of NF-κB to DNA was examined in nuclear extracts using Trans-AM NF-κB ELISA kit. Western blot was performed to detect the effect of curcumin on the expression of uPA. Our results showed that curcumin dose-dependently inhibited (P < 0.05) the proliferation of MCF-7 cells. Meanwhile, the adhesion and invasion ability of MCF-7 cells were sharply inhibited when treated with different concentrations of curcumin. Curcumin also significantly decreased (P < 0.05) the expression of uPA and NF-κB DNA binding activity, respectively. It is concluded that curcumin inhibits the adhesion and invasion of MCF-7 cells through down-regulating the protein expression of uPA via of NF-κB activation. Accordingly, the therapeutic potential of curcumin for breast cancer deserves further study.

Topics: Breast Neoplasms; Cell Adhesion; Cell Line, Tumor; Cell Survival; Curcumin; Disease Progression; DNA, Neoplasm; Female; Humans; Neoplasm Invasiveness; Neoplasm Metastasis; NF-kappa B; Protein Binding; Signal Transduction; Urokinase-Type Plasminogen Activator

The factors responsible for the induction of cell death by dimethoxycurcumin (Dimc), a synthetic analog of curcumin, were assessed in human breast carcinoma MCF7 cells. Initial cytotoxic studies with both curcumin and Dimc using MTT assay indicated their comparable effects. Further, the mechanism of action was explored in terms of oxidative stress, mitochondrial dysfunction, and modulation in the expression of proteins involved in cell cycle regulation and apoptosis. Dimc (5-50 μM) caused generation of reactive oxygen species, reduction in glutathione level, and induction of DNA damage. The mitochondrial dysfunction induced by Dimc was evidenced by the reduction in mitochondrial membrane potential and decrease in cellular energy status (ATP/ADP) monitored by HPLC analysis. The observed decrease in ATP was also supported by the significant suppression of different (α, β, γ, and ε) subunits of ATP synthase. The cytotoxic effect of Dimc was further characterized in terms of induction of S-phase cell cycle arrest and apoptosis, and their relative contribution was found to vary with the treatment concentration of Dimc. The S-phase arrest and apoptosis could also be correlated with the changes in the expressions of cell cycle proteins like p53, p21, CDK4, and cyclin-D1 and apoptotic markers like Bax and Bcl-2. Overall, the results demonstrated that Dimc induced cell death in MCF7 cells through S-phase arrest and apoptosis.

Topics: Antineoplastic Agents; Antioxidants; Apoptosis; Breast Neoplasms; Cell Cycle Proteins; Cell Line, Tumor; Cell Survival; Curcumin; Drug Screening Assays, Antitumor; Female; Humans; Membrane Potential, Mitochondrial; Mitochondria; Reactive Oxygen Species; S Phase Cell Cycle Checkpoints

Curcumin, the active component of turmeric, has been shown to protect against carcinogenesis and prevent tumor development in cancer. In our study, we tested the efficacy of a synthetic curcumin analogue, known as hydrazinocurcumin (HC), in breast cancer cells. The results demonstrated that compared to curcumin, HC was more effective in inhibiting STAT3 phosphorylation and downregulation of an array of STAT3 downstream targets which contributed to suppression of cell proliferation, loss of colony formation, depression of cell migration and invasion as well as induction of cell apoptosis. It was concluded that HC is a potent agent in the inhibition of STAT3 with more favorable pharmacological activity than curcumin, and HC may have translational potential as an effective cancer therapeutic or preventive agent for human breast carcinoma.

Topics: Apoptosis; Breast Neoplasms; Cell Adhesion; Cell Cycle Checkpoints; Cell Growth Processes; Cell Line, Tumor; Cell Movement; Cell Survival; Curcumin; Dose-Response Relationship, Drug; Female; Humans; Hydrazines; Phosphorylation; STAT3 Transcription Factor

Obesity is frequently associated with breast cancer. Such associations are possibly mediated by adipokines. Visfatin, an adipokine, has recently been shown to be related to the development and progression of breast cancer. Therefore, the down-regulation of visfatin may be a novel strategy for breast cancer therapy. Curcumin has anticancer activities by modulating multiple signaling pathways and genes. The purpose of this study was to investigate whether visfatin gene expression is affected by curcumin in human breast cancer cells and to characterize the functional role of visfatin in breast cancer. We found that the mRNA and protein levels of visfatin were down-regulated by curcumin in MDA-MB-231, MDA-MB-468, and MCF-7 breast cancer cells, along with decreased activity of constitutive nuclear factor (NF)-κB. We confirmed the repressive effect of curcumin on visfatin transcription by performing a visfatin promoter-driven reporter assay and identified two putative NF-κB-binding sites on visfatin promoter that are important for this effect. EMSA and chromatin immunoprecipitation analysis indicated the binding of p65 to the visfatin promoter, which was effectively blocked by curcumin. Enforced expression of p65 protein increased visfatin promoter activity, whereas blocking NF-κB signaling suppressed visfatin gene expression. Visfatin could enhance the invasion of MDA-MB-231 cells and also attenuate curcumin-induced inhibition of cell invasion; on the other hand, visfatin knockdown by small interfering RNA led to the reduction of cell invasion. Our data demonstrate, for the first time, that curcumin down-regulates visfatin gene expression in human breast cancer cells by a mechanism that is, at least in part, NF-κB dependent and suggest that visfatin may contribute to breast cancer cell invasion and link obesity to breast cancer development and progression.

Topics: Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cell Line, Tumor; Curcumin; Cytokines; Down-Regulation; Female; Gene Expression Regulation, Neoplastic; Humans; Neoplasm Invasiveness; NF-kappa B; Nicotinamide Phosphoribosyltransferase; Obesity; Promoter Regions, Genetic; Response Elements

Curcumin nanoparticles of less than 50 nm in diameter are accessible using a continuous flow microfluidic rotating tube processor (RTP) under scalable conditions, at room temperature. A mixture of DDAB and Pluronic F127 renders higher stability of the curcumin nanoparticles in physiological pH 7.4 for up to eight hours. The nanoparticles have enhanced cytotoxicity in estrogens receptor negative and positive breast cancer cell lines compared with free curcumin.

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Curcumin; Drug Carriers; Female; Humans; Hydrogen-Ion Concentration; Microfluidic Analytical Techniques; Nanoparticles; Poloxamer; Quaternary Ammonium Compounds; Receptors, Estrogen

Co-encapsulated doxorubicin (DOX) and curcumin (CUR) in poly(butyl cyanoacrylate) nanoparticles (PBCA-NPs) were prepared with emulsion polymerization and interfacial polymerization. The mean particle size and mean zeta potential of CUR-DOX-PBCA-NPs were 133 ± 5.34 nm in diameter and +32.23 ± 4.56 mV, respectively. The entrapment efficiencies of doxorubicin and curcumin were 49.98 ± 3.32% and 94.52 ± 3.14%, respectively. Anticancer activities and reversal efficacy of the formulations and various combination approaches were assessed using 3-[4,5-dimethylthiazol-2-yl] 2,5-diphenyltetrazolium bromide assay and western blotting. The results showed that the dual-agent loaded PBCA-NPs system had the similar cytotoxicity to co-administration of two single-agent loaded PBCA-NPs (DOX-PBCA-NPs+CUR-PBCA-NPs), which was slightly higher than that of the free drug combination (DOX+CUR) and one free drug/another agent loaded PBCA-NPs combination (DOX+CUR-PBCA-NPs or CUR+DOX-PBCA-NPs). The simultaneous administration of doxorubicin and curcumin achieved the highest reversal efficacy and down-regulation of P-glycoprotein in MCF-7/ADR cell lines, an MCF-7 breast carcer cell line resistant to adriamycin. Multidrug resistance can be enhanced by combination delivery of encapsulated cytotoxic drugs and reversal agents.

Topics: Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Breast Neoplasms; Calorimetry, Differential Scanning; Cell Line, Tumor; Chemistry, Pharmaceutical; Chitosan; Chromatography, Gel; Curcumin; Down-Regulation; Doxorubicin; Drug Carriers; Drug Combinations; Drug Compounding; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Enbucrilate; Female; Humans; Nanoparticles; Nanotechnology; Particle Size; Spectroscopy, Fourier Transform Infrared; Technology, Pharmaceutical

The next generation magnetic nanoparticles (MNPs) with theranostic applications have attracted significant attention and will greatly improve nanomedicine in cancer therapeutics. Such novel MNP formulations must have ultra-low particle size, high inherent magnetic properties, effective imaging, drug targeting, and drug delivery properties. To achieve these characteristic properties, a curcumin-loaded MNP (MNP-CUR) formulation was developed.. MNPs were prepared by chemical precipitation method and loaded with curcumin (CUR) using diffusion method. The physicochemical properties of MNP-CUR were characterized using dynamic light scattering, transmission electron microscopy, and spectroscopy. The internalization of MNP-CUR was achieved after 6 hours incubation with MDA-MB-231 breast cancer cells. The anticancer potential was evaluated by a tetrazolium-based dye and colony formation assays. Further, to prove MNP-CUR results in superior therapeutic effects over CUR, the mitochondrial membrane potential integrity and reactive oxygen species generation were determined. Magnetic resonance imaging capability and magnetic targeting property were also evaluated.. MNP-CUR exhibited individual particle grain size of ~9 nm and hydrodynamic average aggregative particle size of ~123 nm. Internalized MNP-CUR showed a preferential uptake in MDA-MB-231 cells in a concentration-dependent manner and demonstrated accumulation throughout the cell, which indicates that particles are not attached on the cell surface but internalized through endocytosis. MNP-CUR displayed strong anticancer properties compared to free CUR. MNP-CUR also amplified loss of potential integrity and generation of reactive oxygen species upon treatment compared to free CUR. Furthermore, MNP-CUR exhibited superior magnetic resonance imaging characteristics and significantly increased the targeting capability of CUR.. MNP-CUR exhibits potent anticancer activity along with imaging and magnetic targeting capabilities. This approach can be extended to preclinical and clinical use and may have importance in cancer treatment and cancer imaging in the future. Further, if these nanoparticles can functionalize with antibody/ligands, they will serve as novel platforms for multiple biomedical applications.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Curcumin; Drug Delivery Systems; Female; Humans; Magnetic Resonance Imaging; Magnetite Nanoparticles; Membrane Potential, Mitochondrial; Microscopy, Electron, Transmission; Nanomedicine; Reactive Oxygen Species

In this study, we investigated the role of Ca(2+) in curcumin-induced paraptosis, a cell death mode that is accompanied by dilation of mitochondria and the endoplasmic reticulum (ER). Curcumin induced mitochondrial Ca(2+) overload selectively in the malignant breast cancer cells, but not in the normal breast cell, contributing to the dilation of mitochondria/ER and subsequent paraptotic cell death. In addition, we found that simultaneous inhibition of the mitochondrial Na(+)/Ca(2+) exchanger (mNCX) and proteasomes can trigger a sustained mitochondrial Ca(2+) overload and effectively induce paraptosis in malignant breast cancer cells.

Topics: Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Breast Neoplasms; Calcium; Cell Death; Cell Line, Tumor; Clonazepam; Curcumin; Dose-Response Relationship, Drug; Endoplasmic Reticulum; Female; Humans; Mitochondria; Protease Inhibitors; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Pyrazines; Sodium-Calcium Exchanger; Thiazepines; Time Factors

A one-step synthesis of a curcumin-derived hydrogel (curcumin content of 25-75 mol %) is reported. Curcumin is incorporated into the hydrogel backbone and cross-linked through biodegradable carbonate linkages. Curcumin as a part of the polymer backbone is protected from oxidation and degradation, while hydrogel hydrolysis results in the release of active curcumin. Nontoxic poly(ethylene glycol) and desaminotyrosyl-tyrosine ethyl ester are used to tune the hydrophilic/hydrophobic hydrogel properties. In this way, hydrogels with a wide range of physical properties including water-uptake (100-550%) and compression moduli (7-100 kPa) were obtained. Curcumin release is swelling-controlled and could be extended to 80 days. In vitro, curcumin-derived hydrogels showed selective cytotoxicity against MDA-MB-231 (IC(50) 9 μM) breast cancer cells but no cytotoxicity to noncancerous quiescent human dermal fibroblasts even at high curcumin concentrations (160 μM). One possible application of these curcumin-derived hydrogels is as soft tissue filler after surgical removal of cancerous tissue.

Topics: Absorbable Implants; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Survival; Coculture Techniques; Curcumin; Drug Carriers; Elastic Modulus; Female; Humans; Hydrogels; Mammaplasty; Mammary Glands, Human; Phosgene; Polyethylene Glycols; Porosity; Regeneration; Tissue Engineering; Transition Temperature; Wettability

There is a need for the development of new, safe and efficacious drug therapies for the treatment of estrogen receptor (ER)-negative breast cancers. RL71 is a second-generation curcumin analog that exhibits potent cytotoxicity towards a variety of ER-negative breast cancer cells. Therefore, we have further examined the mechanism of this anticancer activity in three different ER-negative breast cancer cell lines. The mechanistic studies demonstrated that RL71 (1 µM) induced cell cycle arrest in the G2/M phase of the cell cycle. Moreover, RL71 (1 µM) caused 35% of SKBr3 cells to undergo apoptosis after 48 h and this effect was time-dependent. This correlated with an increase in cleaved caspase-3 as shown by western blotting. RL71 (1 µM) also decreased HER2/neu phosphorylation and increased p27 in SKBr3 cells. While in MDA-MB-231 and MDA-MB-468 cells RL71 (1 µM) significantly decreased Akt phosphorylation and transiently increased the stress kinases JNK1/2 and p38 MAPK. In addition, RL71 exhibited anti-angiogenic potential in vitro as it inhibited HUVEC cell migration and the ability of these cells to form tube-like networks. RL71 (8.5 mg/kg) was also orally bioavailable as it produced a peak plasma concentration of 0.405 µg/ml, 5 min after oral drug administration. Thus, our findings provide evidence that RL71 has potent anticancer activity and has potential to be further developed as a drug for the treatment of ER-negative breast cancer.

Topics: Animals; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Caspase 3; Cell Line, Tumor; Cell Movement; Curcumin; Diarylheptanoids; Down-Regulation; Female; G2 Phase Cell Cycle Checkpoints; Human Umbilical Vein Endothelial Cells; Humans; JNK Mitogen-Activated Protein Kinases; Mice; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Proliferating Cell Nuclear Antigen; Proto-Oncogene Proteins c-akt; Receptor, ErbB-2; Receptors, Estrogen; Signal Transduction

Delivery of therapeutic agents to bone is crucial in several diseases such as osteoporosis, Paget's disease, myeloproliferative diseases, multiple myeloma as well as skeletal metastasizing cancers. Prevention of cancer growth and lowering the cancer induced bone resorption is important in the treatment of bone metastasizing cancers. Keeping in mind the low diffusivity and availability of cell surface targets on cancer cells, we designed a targeted system to deliver chemotherapeutic agents to the bone microenvironment as an approach to tissue targeting using alendronate (Aln). We co-encapsulated curcumin and bortezomib in the PLGA nanoparticles to further enhance the therapeutic efficiency and overall clinical outcome. These multifunctional nanoparticles were characterized for particle size, morphology and drug encapsulation. The particles were spherical with smooth surface and had particle size of 235 ± 70.30 nm. We validated the bone targeting ability of these nanoparticles in vitro. Curcumin and bortezomib are known to have synergistic effect in inhibition of growth of cancer; however there was no synergism in the anti-osteoclastogenic activity of these agents. Surprisingly, curcumin by itself had significant inhibition of osteclastogenic activity. In vivo non-invasive bioimaging showed higher localization of Aln-coated nanoparticles to the bone compared to control groups, which was further confirmed by histological analysis. Aln-coated nanoparticles protected bone resorption and decreased the rate of tumor growth as compared to control groups in an intraosseous model of bone metastasis. Our data show efficient attachment of Aln on the surface of nanoparticles which could be used as a drug carrier for preferential delivery of multiple therapeutic agents to bone microenvironment.

Topics: Alendronate; Animals; Antineoplastic Agents; Bone and Bones; Bone Neoplasms; Boronic Acids; Bortezomib; Breast Neoplasms; Curcumin; Drug Carriers; Female; Humans; Lactic Acid; Mice; Mice, Nude; Nanoparticles; Neoplasm Metastasis; Osteoporosis; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Pyrazines

Studies indicate that extracts and purified components, including carnosic acid, from the herb rosemary display significant growth inhibitory activity on a variety of cancers.. This paper examines the ability of rosemary/carnosic acid to inhibit the growth of human breast cancer cells and to synergize with curcumin.. To do this, we treated human breast cancer cells with rosemary/carnosic acid and assessed effects on cell proliferation, cell cycle distribution, gene expression patterns, activity of the purified Na/K ATPase and combinations with curcumin.. Rosemary/carnosic acid potently inhibits proliferation of ER-negative human breast cancer cells and induces G1 cell cycle arrest. Further, carnosic acid is selective for MCF7 cells transfected for Her2, indicating that Her2 may function in its action. To reveal primary effects, we treated ER-negative breast cancer cells with carnosic acid for 6h. At a low dose, 5 μg/ml (15 μM), carnosic acid activated the expression of 3 genes, induced through the presence of antioxidant response elements, including genes involved in glutathione biosynthesis (CYP4F3, GCLC) and transport (SLC7A11). At a higher dose, 20 μg/ml, carnosic acid activated the expression of antioxidant (AKR1C2, TNXRD1, HMOX1) and apoptosis (GDF15, PHLDA1, DDIT3) genes and suppressed the expression of inhibitor of transcription (ID3) and cell cycle (CDKN2C) genes. Carnosic acid exhibits synergy with turmeric/curcumin. These compounds inhibited the activity of the purified Na-K-ATPase which may contribute to this synergy.. Rosemary/carnosic acid, alone or combined with curcumin, may be useful to prevent and treat ER-negative breast cancer.

Topics: Abietanes; Antineoplastic Agents, Phytogenic; Antioxidants; Apoptosis; Breast Neoplasms; Cell Cycle Checkpoints; Cell Proliferation; Curcuma; Curcumin; Drug Synergism; Female; Gene Expression; Glutathione; Humans; Inhibitor of Differentiation Proteins; MCF-7 Cells; Neoplasm Proteins; Phytotherapy; Plant Extracts; Receptor, ErbB-2; Receptors, Estrogen; Rosmarinus

Curcumin (diferuloylmethane) is a polyphenol derived from the plant turmeric (Curcuma longa), which is commonly used as a spice. Although anti-carcinogenic, anti-oxidant, anti-inflammation, and anti-angiogenic properties have been reported, the effect of curcumin on breast cancer metastasis is unknown. Matrix metalloproteinase-9 (MMP-9) is a major component in cancer cell invasion. In this study, we investigated the inhibitory effect of curcumin on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced MMP-9 expression and cell invasion and the molecular mechanisms involved in MCF-7 cells. Our results showed that curcumin inhibits TPA-induced MMP-9 expression and cell invasion through suppressing NF-κB and AP-1 activation. Also, curcumin strongly repressed the TPA-induced phosphorylation of p38 and JNK and inhibited TPA-induced translocation of PKCα from the cytosol to the membrane, but did not affect the translocation of PKCδ. These results indicate that curcumin-mediated inhibition of TPA-induced MMP-9 expression and cell invasion involves the suppression of the PKCα, MAPK and NF-κB/AP-1 pathway in MCF-7 cells. Curcumin may have potential value in restricting breast cancer metastasis.

Topics: Antineoplastic Agents, Phytogenic; Biological Transport; Breast Neoplasms; Cell Movement; Curcuma; Curcumin; Female; Humans; JNK Mitogen-Activated Protein Kinases; Matrix Metalloproteinase 9; MCF-7 Cells; Neoplasm Metastasis; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Phytotherapy; Plant Extracts; Protein Kinase C-alpha; Signal Transduction; Tetradecanoylphorbol Acetate; Transcription Factor AP-1

Novel ruthenium-letrozole complexes have been prepared, and cell viability of two human cancer cell types (breast and glioblastoma) was determined. Some ruthenium compounds are known for their cytotoxicity to cancer cells, whereas letrozole is an aromatase inhibitor administered after surgery to post-menopausal women with hormonally responsive breast cancer. A significant in vitro activity was established for complex 5·Let against breast cancer MCF-7 cells and significantly lower activity against glioblastoma U251N cells. The activity of 5·Let was even higher than that of 4, a compound analogous to the well-known drug RAPTA-C. Results from the combination of 5·Let (or 4) with 3-methyladenine (3-MA) or with curcumin, respectively, revealed that the resultant cancer cell death likely involves 5·Let-induced autophagy.

Topics: Adenine; Adenocarcinoma; Antineoplastic Agents; Aromatase Inhibitors; Autophagy; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Coordination Complexes; Crystallography, X-Ray; Curcumin; Drug Interactions; Drug Screening Assays, Antitumor; Female; Glioblastoma; Humans; Letrozole; Nitriles; Ruthenium; Stereoisomerism; Structure-Activity Relationship; Triazoles

Curcumin (CM) possesses anti-cancer activity against a variety of tumors. Matrix metalloproteinases (MMPs) play an important role in remodeling the extracellular matrix and their activities are regulated by tissue inhibitor of metalloproteinases (TIMPs) family. Control of MMP and TIMP activity are now of great significance. In this study, the effect of CM is investigated on metastatic MMPs and anti-metastatic TIMPs genes on MDA breast cancer cells cultured in a mixture of DMEM and Ham's F12 medium and treated with different concentrations of CM (10, 20 and 40 μM for various lengths of time. Reverse transcription followed by quantitative real time PCR was used to detect the gene expression levels of MMPs and TIMPs in CM-treated versus untreated cases and the data were analyzed by one-way ANOVA. At high concentrations of curcumin, TIMP-1, -2, -3 and -4 genes were up-regulated after 48 hours of treatment, their over-expression being accompanied by down-regulation of MMP-2 and MMP-9 gene expression levels in a concentration- and time-dependent manner. These results suggest that curcumin plays a role in regulating cell metastasis by inhibiting MMP-2 and MMP-9 and up-regulating TIMP1 and TIMP4 gene expression in breast cancer cells.

Topics: Breast Neoplasms; Cell Line, Tumor; Curcumin; Down-Regulation; Female; Gene Expression Regulation, Neoplastic; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Tissue Inhibitor of Metalloproteinases; Up-Regulation

Curcuminoids (including curcumin) are natural antioxidants demonstrating potent chemopreventive properties against several forms of cancer. This study investigated the antiproliferative and induced apoptotic effects of curcuminoids on three cell lines isolated from human breast adenocarcinoma and ductal carcinoma (MDA-MB-231, MDA-MB-435S, and MCF-7).. This study developed a highly sensitive, reproducible assay method using high-pressure liquid chromatography to quantify the cellular uptake of curcuminoids by breast cancer cells and quantitate its effect on inhibition of proliferation and activation of apoptosis in breast cancer cells.. Results indicate that curcuminoids inhibited cell proliferation and activation of apoptosis in the cell lines in this study. Both effects were observed to increase in proportion to the cellular uptake of curcuminoids; cellular uptake increased following an increase in the dosage of curcuminoids.. The inhibition of proliferation and increased apoptosis of breast cancer cells appears to be associated with the uptake of curcuminoids by cancer cells.

Topics: Adenocarcinoma; Antineoplastic Agents; Apoptosis; Biological Availability; Breast Neoplasms; Carcinoma, Ductal, Breast; Cell Line, Tumor; Cell Proliferation; Chromatography, High Pressure Liquid; Curcumin; Diarylheptanoids; Dose-Response Relationship, Drug; Female; Humans

Reactivation of tumor suppressor genes (TSGs) involved in carcinogenesis by nontoxic bioactive food component represents a promising strategy for cancer chemoprevention. Recently, curcumin has been demonstrated to inhibit a bacterial DNA methyltransferase (M. Sss I) activity, induce global DNA hypomethylation in leukemia cells, and reactivate several hypermethylation silenced genes in lung and prostate cancer cells. Herein, we demonstrated that curcumin can enhance the mRNA and protein levels of ras-association domain family protein 1A (RASSF1A), 1 hypermethylation-silenced TSG, and decrease its promoter methylation in breast cancer cells. Mechanistic study demonstrated that curcumin can decrease DNA methylation activity of nuclear extract and downregulate the mRNA and protein levels of DNMT1 in MCF-7 cells, which may be associated with curcumin-induced disruption of NF-κB/Sp1 complex bound to the promoter region of DNMT1. Altogether, this study reveals a novel molecular mechanism of curcumin as a chemo-preventive agent for breast cancer through hypomethylation reactivation of RASSF1A.

Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Curcumin; DNA Methylation; Down-Regulation; Female; Humans; MCF-7 Cells; Mice; Mice, Nude; Promoter Regions, Genetic; Repressor Proteins; RNA, Messenger; Transcriptional Activation; Tumor Suppressor Proteins; Xenograft Model Antitumor Assays

Curcumin exhibits growth-suppressive activity against a variety of cancer cells, but low bioavailability prevents its use in chemotherapeutic applications. One strategy for circumventing this problem has been the creation of synthetic analogs. In this study we synthesized an analog of curcumin bis-1,7-2(hydroxyphenil)-hepta-1,6diene-3,5diore (BDMC-A) and investigated its anti-breast cancer property.. We compared the impact of bis-1,7-2(hydroxyphenil)-hepta-1,6diene-3,5diore (BDMC-A) with that of curcumin in human breast cancer cell line MCF-7. MTT [3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide] cell viability assay was used to examine the cell viability/proliferation. LDH assay and cell counts were performed to assess the cytotoxicity and anti-proliferative effects of the compound respectively. Flow cytometry followed by Western blot were performed to investigate the cell cycle distribution.. BDMC-A has an inhibitory effect on MCF-7 cells comparably equivalent to that of curcumin as determined by MTT assay. Cytotoxicity of the cells by both curcumin and BDMC-A were confirmed by LDH release assay and cell count assay. Flow cytometric studies showed accumulation of cells in the G2/M phase which confirms the cell cycle arrest. This was further confirmed by immunoblotting of the protein Cyclin D1, whose expression were found to be decreased in both curcumin and BDMC-A treatment.. The results indicate that the curcumin analog exhibit potent inhibitory activity which is comparable to that of curcumin in human breast cancer cells. Since the solubility of BDMC-A was higher in aqueous medium, it is expected to be more bioavailable, and hence more active in vivo. Further evaluation might reveal its role on various molecular targets.

Topics: Antineoplastic Agents, Phytogenic; Biomarkers, Tumor; Blotting, Western; Breast Neoplasms; Cell Proliferation; Cell Survival; Curcumin; Cyclin D1; Dose-Response Relationship, Drug; Female; Flow Cytometry; G2 Phase Cell Cycle Checkpoints; Humans; L-Lactate Dehydrogenase; MCF-7 Cells; Time Factors

To evaluate the effects of curcumin on matrixmetalloproteinase-9 (MMP-9) and invasion ability induced by transforming growth factor-β1 (TGF-β1) in MDA-MB-231 cells and potential mechanisms.. Human breast cancer MDA- MB-231 cells were used with the CCK-8 assay to measure the cytotoxicity of curcumin. After treatment with 10 ng/ml TGF-β1, with or without curcumin (≤10 μM), cell invasion was checked by transwell chamber. The effects of curcumin on TGF-β1-stimulated MMP-9 and phosphorylation of Smad2, extracellular-regulated kinase (ERK), and p38 mitogen activated protein kinases (p38MAPK) were examined by Western blotting. Supernatant liquid were collected to analyze the activity of MMP-9 via zymography. Following treatment with PD98059, a specific inhibitor of ERK, and SB203580, a specific inhibitor of p38MAPK, Western blotting and zymography were employed to examine MMP-9 expression and activity, respectively.. Low dose curcumin (≤10 μM) did not show any obvious toxicity to the cells, while 0~10 μmol/L caused a concentration-dependent reduction in cell invasion provoked by TGF-β1. Curcumin also markedly inhibited TGF-β1-regulated MMP-9 and activation of Smad2, ERK1/2 and p38 in a dose- and time-dependent manner. Additionally, PD98059, but not SB203580, showed a similar pattern of inhibition of MMP-9 expression.. Curcumin inhibited TGF-β1-stimulated MMP-9 and the invasive phenotype in MDA-MB-231 cells, possibly associated with TGF-β/Smad and TGF-β/ERK signaling.

Topics: Antineoplastic Combined Chemotherapy Protocols; Blotting, Western; Breast Neoplasms; Cell Movement; Cell Proliferation; Curcumin; Enzyme Inhibitors; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Matrix Metalloproteinase 9; Neoplasm Invasiveness; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Smad2 Protein; Transforming Growth Factor beta1; Tumor Cells, Cultured

Recent evidence suggests that breast cancer is one of the most common forms of malignancy in females, and metastasis from the primary cancer site is the main cause of death. Aromatic (ar)-turmerone is present in Curcuma longa and is a common remedy and food. In the present study, we investigated the inhibitory effects of ar-turmerone on expression and enzymatic activity levels of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced matrix metalloproteinase (MMP)-9 and cyclooxygenaase-2 (COX-2) in breast cancer cells. Our data indicated that ar-turmerone treatment significantly inhibited enzymatic activity and expression of MMP-9 and COX-2 at non-cytotoxic concentrations. However, the expression of tissue inhibitor of metalloproteinase (TIMP)-1, TIMP-2, MMP-2, and COX-1 did not change upon ar-turmerone treatment. We found that ar-turmerone inhibited the activation of NF-κB, whereas it did not affect AP-1 activation. Moreover, The ChIP assay revealed that in vivo binding activities of NF-κB to the MMP-9 and COX-2 promoter were significantly inhibited by ar-turmerone. Our data showed that ar-turmerone reduced the phosphorylation of PI3K/Akt and ERK1/2 signaling, whereas it did not affect phosphorylation of JNK or p38 MAPK. Thus, transfection of breast cancer cells with PI3K/Akt and ERK1/2 siRNAs significantly decreased TPA-induced MMP-9 and COX-2 expression. These results suggest that ar-turmerone suppressed the TPA-induced up-regulation of MMP-9 and COX-2 expression by blocking NF-κB, PI3K/Akt, and ERK1/2 signaling in human breast cancer cells. Furthermore, ar-turmerone significantly inhibited TPA-induced invasion, migration, and colony formation in human breast cancer cells.

Topics: Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Cell Survival; Chromatin Immunoprecipitation; Curcuma; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Enzyme Activation; Female; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Ketones; MAP Kinase Signaling System; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Promoter Regions, Genetic; RNA, Small Interfering; Sesquiterpenes; Tetradecanoylphorbol Acetate; Tissue Inhibitor of Metalloproteinase-1; Transfection

Previous studies have reported that the Curcuma wenyujin Y.H. Chen et C. Ling extract, which has a high furanodiene content, showed anti-cancer effects in breast cancer cells in vitro. The present study was designed to evaluate the in vitro and in vivo anti-cancer activity of furanodiene.. The in vitro effects of furanodiene were examined on two human breast cancer cell lines, MCF-7 and MDA-MB-231 cells. Assays of proliferation, LDH release, mitochondrial membrane potential (ΔΨm), cell cycle distribution, apoptosis and relevant signaling pathways were performed. The in vivo effect was determined with MCF7 tumor xenograft model in nude mice.. Furanodiene significantly inhibited the proliferation and increased the LDH release in both cell lines in a dose-dependent manner. ΔΨm depolarization, chromatin condensation, and DNA fragmentation were also observed after furanodiene treatment. Furanodiene dose-dependently induced cell cycle arrest at the G0/G1 phase. The protein expressions of p-cyclin D1, total cyclin D1, p-CDK2, total CDK2, p-Rb, total Rb, Bcl-xL, and Akt were significantly inhibited by furanodiene, whereas the protein expressions of Bad and Bax, and the proteolytic cleavage of caspase-9, caspase-7, and poly-ADP-ribose polymerase (PARP) were dramatically increased. Furthermore, the z-VAD-fmk markedly reversed the furanodiene-induced cell cytotoxicity, the proteolytic cleavage of caspase-9, and DNA fragmentation but did not affect the proteolytic cleavage of PARP, whereas the Akt inhibitor VIII increased the furanodiene-induced cytotoxicity and PARP cleavage. In addition, furanodiene dose-dependently suppressed the tumor growth in vivo, achieving 32% and 54% inhibition rates after intraperitoneal injection of 15 mg/kg and 30 mg/kg, respectively.. Taken together, we concluded that furanodiene suppresses breast cancer cell growth both in vitro and in vivo and could be a new lead compound for breast cancer chemotherapy.

Topics: Amino Acid Chloromethyl Ketones; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; bcl-2-Associated X Protein; bcl-Associated Death Protein; Breast Neoplasms; Caspase 7; Caspase 9; Cell Line, Tumor; Cell Proliferation; Curcuma; DNA Fragmentation; Female; Furans; G1 Phase Cell Cycle Checkpoints; Heterocyclic Compounds, 2-Ring; Humans; L-Lactate Dehydrogenase; MCF-7 Cells; Membrane Potential, Mitochondrial; Mice; Mice, Inbred BALB C; Mice, Nude; Poly(ADP-ribose) Polymerases; Proto-Oncogene Proteins c-akt; Transplantation, Heterologous

Estrogen receptor (ER)-negative breast cancer is an aggressive form that currently requires more drug treatment options. Thus, we have further modified cyclohexanone derivatives of curcumin and examined them for cytotoxicity towards ER-negative human breast cancer cells. Two of the analogs screened elicited increased cytotoxic potency compared to curcumin and other previously studied derivatives. Specifically, 2,6-bis(pyridin-3-ylmethylene)-cyclohexanone (RL90) and 2,6-bis(pyridin-4-ylmethylene)-cyclohexanone (RL91) elicited EC(50) values of 1.54 and 1.10 µM, respectively, in MDA-MB-231 cells and EC(50) values of 0.51 and 0.23 in SKBr3 cells. All other new compounds examined were less potent than curcumin, which elicited EC(50) values of 7.6 and 2.4 µM in MDA-MB-231 and SKBr3 cells, respectively. Mechanistic analyses demonstrated that RL90 and RL91 significantly induced G(2)/M-phase cell cycle arrest and apoptosis. RL90 and RL91 also modulated the expression of key cell signaling proteins, specifically, in SKBr3 cells, protein levels of Her-2, Akt, and NFκB were decreased in a time-dependent manner, while activity of stress kinases JNK1/2 and P38 MAPK were increased. Signaling events in MDA-MB-231 cells were differently implicated, as EGFR protein levels were decreased and activity of GSK-3β transiently decreased, while β-catenin protein level and activity of P38 MAPK, Akt, and JNK1/2 were transiently increased. In conclusion replacement of the phenyl group of cyclohexanone derived curcumin derivatives with heterocyclic rings forms a class of second-generation analogs that are more potent than both curcumin and other derivatives. These new derivatives provide a platform for the further development of drugs for the treatment of ER-negative breast cancer.

Topics: Breast Neoplasms; Cell Death; Cell Division; Cell Line, Tumor; Curcumin; Cyclohexanones; Drug Screening Assays, Antitumor; Female; G2 Phase; Heterocyclic Compounds; Humans; Neoplasm Proteins; Receptors, Estrogen; Signal Transduction

Curcumin (CM), a well-known dietary pigment derived from Curcuma longa L., possess anticancer activities against a variety of tumors including human breast carcinoma. In combination with docetaxel, CM has been used in breast cancer management in the clinic. In order to explore the possible mechanism of anticancer activity of CM, in the present study, we aimed to identify proteins involved in the anticancer activity of CM in human breast cancer cell line MCF-7 using the two-dimensional electrophoresis (2-DE)-based proteomic analysis. MCF-7 cells were cultured at 37°C in an atmosphere of 5.0% CO(2). All the following experiments were repeated three times. Cell viability assay showed that after a 48-h incubation CM dose-dependently inhibited cell growth with an IC(50) value of 47.42 μM. Treatment of CM at 47.42 μM for 48 h induced apoptosis as determined by nuclear morphologic changes of Hoechst stained cells and flow cytometric analysis of Annexin V-FITC/PI stained cells. Proteomic analysis identified 12 differentially expressed proteins which contributed to multiple functional activities such as DNA transcription, mRNA splicing and translation, amino acid synthesis, protein synthesis, folding and degradation, lipid metabolism, glycolysis, and cell motility. Among them 7 proteins were up-regulated and 5 down-regulated. The up-regulated ones were verified by quantitative real-time PCR. The down-regulated proteins, TDP-43, SF2/ASF and eIF3i, as well as up-regulated ones, 3-PGDH, ERP29, and platelet-activating factor acetylhydrolase IB subunit beta positively contribute to the anticancer activity of CM in MCF-7 cells. These molecules are implicated in the bioactivities of CM for the first time. The findings of this study would shed new insights for systematically understanding the mechanisms of CM in breast cancer intervention.

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Cycle; Cell Growth Processes; Cell Line, Tumor; Curcuma; Curcumin; Electrophoresis, Gel, Two-Dimensional; Female; Gene Expression Regulation, Neoplastic; Humans; Neoplasm Proteins; Phytotherapy; Proteomics; RNA, Messenger

The morphology changes, in particular the organization of microtubules in mammalian nonmalignant HMEC 184A1 and cancerous MCF-7 cells during curcumin treatment have been investigated by utilizing multiphoton, fluorescence, and atomic force (AFM) microscopies. Fluorescence microscopy reveals formation of ring-like structures of microtubules circumscribing the nuclear area in HMEC 184A1 cells after treatment, while in MCF-7 cells, no important changes were observed. Topography analyses of fixed HMEC 184A1 and MCF-7 before and after treatment with curcumin were performed using AFM and the effect of the employed cells' fixation method was investigated on MCF-7 cells. Due to its indepth optical sectioning capacity multiphoton microscopy provided valuable complementary information on curcumin's effect on both cells' types. Combining information provided by AFM and optical fluorescence and biphoton microscopes allows us to gain a better understanding of the cells and their curcumin-induced changes, especially for microtubules which are the main target of antitumor chemotherapy treatments. Our multimicroscopic study demonstrates that 6 h incubation with curcumin does not induce significant modifications in the interphase microtubules in the malignant MCF7cell, whereas it has measurable effects on those of the nonmalignant HMEC 184A1 cells, revealing also morphology modifications over the nuclear area of these cells.

Topics: Breast Neoplasms; Cell Line, Tumor; Curcumin; Female; Humans; Mammary Glands, Human; Microscopy; Microscopy, Atomic Force; Microscopy, Fluorescence; Microtubules; Photons

Breast cancer is a collection of diseases in which molecular phenotypes can act as both indicators and mediators of therapeutic strategy. Therefore, candidate therapeutics must be assessed in the context of multiple cell lines with known molecular phenotypes. Docosahexaenoic acid (DHA) and curcumin (CCM) are dietary compounds known to antagonize breast cancer cell proliferation. We report that these compounds in combination exert a variable antiproliferative effect across multiple breast cell lines, which is synergistic in SK-BR-3 cells and triggers cell signaling events not predicted by the activity of either compound alone.. Dose response curves for CCM and DHA were generated for five breast cell lines. Effects of the DHA+ CCM combination on cell proliferation were evaluated using varying concentrations, at a fixed ratio, of CCM and DHA based on their individual ED₅₀. Detection of synergy was performed using nonlinear regression of a sigmoid dose response model and Combination Index approaches. Cell molecular network responses were investigated through whole genome microarray analysis of transcript level changes. Gene expression results were validated by RT-PCR, and western blot analysis was performed for potential signaling mediators. Cellular curcumin uptake, with and without DHA, was analyzed via flow cytometry and HPLC.. CCM+DHA had an antiproliferative effect in SK-BR-3, MDA-MB-231, MDA-MB-361, MCF7 and MCF10AT cells. The effect was synergistic for SK-BR-3 (ER⁻ PR⁻ Her2⁺) relative to the two compounds individually. A whole genome microarray approach was used to investigate changes in gene expression for the synergistic effects of CCM+DHA in SK-BR-3 cells lines. CCM+DHA triggered transcript-level responses, in disease-relevant functional categories, that were largely non-overlapping with changes caused by CCM or DHA individually. Genes involved in cell cycle arrest, apoptosis, inhibition of metastasis, and cell adhesion were upregulated, whereas genes involved in cancer development and progression, metastasis, and cell cycle progression were downregulated. Cellular pools of PPARγ and phospho-p53 were increased by CCM+DHA relative to either compound alone. DHA enhanced cellular uptake of CCM in SK-BR-3 cells without significantly enhancing CCM uptake in other cell lines.. The combination of DHA and CCM is potentially a dietary supplemental treatment for some breast cancers, likely dependent upon molecular phenotype. DHA enhancement of cellular curcumin uptake is one potential mechanism for observed synergy in SK-BR-3 cells; however, transcriptomic data show that the antiproliferation synergy accompanies many signaling events unique to the combined presence of the two compounds.

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Curcumin; Docosahexaenoic Acids; Dose-Response Relationship, Drug; Drug Synergism; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; PPAR gamma; Signal Transduction; Tumor Suppressor Protein p53

The F-box protein S-phase kinase-associated protein 2 (Skp2), which acts as an oncogene through targeting p27 for degradation, is overexpressed in many different human cancers. Skp2 can play an important role in breast cancer progression and may also be a novel molecular target for the treatment of breast cancer, especially estrogen receptor (ER)/human epidermal growth factor 2 (HER2) negative breast cancers. Unfortunately, specific drugs that target Skp2 are unavailable at present. Therefore, it is important to explore whether commonly used chemopreventive agents may downregulate Skp2 expression. In this study, we examined the effects of 1,2,3,4,6-penta-O-galloyl-β-D-glucose (pentagalloylglucose, 5gg), quercetin, curcumin and lycopene on the expression of Skp2 in MDA-MB-231 (ER/HER2-negative) and BT474 (ER-negative/HER2-positive) cells. We found that all four phytochemicals studied induced cell growth inhibition in MDA-MB-231 cells. The mechanism of the initial growth inhibitory events involves blocking the cell cycle progression. Further, we found that quercetin and curcumin induced growth arrest by inhibition of Skp2, and induced p27 expression in MDA-MB-231 cells. However, the decrease in Skp2 levels in cells treated with 5gg or lycopene did not translate to p27 upregulation. Consequently, the downregulation of Skp2 did not always correlate with the upregulation of p27, suggesting that phytochemical-dependent downregulation of Skp2 can influence cell growth in several ways. Several studies have demonstrated that Skp2 directs the ubiquitylation and subsequent degradation of forkhead box protein O1 (FoxO1). Furthermore, our results reveal that FoxO1 protein was increased after 5gg, quercetin, curcumin and lycopene treatment. The therapeutic strategies designed to reduce Skp2 may therefore play an important clinical role in treatment of breast cancer cells, especially ER/HER2-negative breast cancers.

Topics: Breast Neoplasms; Carotenoids; Cell Cycle; Cell Line, Tumor; Curcumin; Down-Regulation; Female; Humans; Hydrolyzable Tannins; Lycopene; Quercetin; S-Phase Kinase-Associated Proteins

In this work we prepared and evaluated the curcumin loaded fibrinogen nanoparticles (CRC-FNPs) as a novel drug delivery system for cancer therapy. These novel CRC-FNPs were prepared by a two-step co-acervation method using calcium chloride as the cross-linker. The prepared nanoparticles were characterized using dynamic light scattering (DLS), atomic force microscopy (AFM), Fourier transform infrared spectroscopy (FT-IR), thermogravimetry (TG), differential thermal analysis (DTA) and X-ray diffraction (XRD) studies. DLS studies showed that the particle size of CRC-FNPs was in the range of 150-200 nm. The loading efficiency (LE) and in vitro drug release were studied using UV spectrophotometer. The LE was found to be 90%. The cytotoxicity was studied using L929 (mouse fibroblast), PC3 (prostate) and MCF7 (breast) cancer cell lines by MTT assay, which confirmed that CRC-FNPs were comparatively non toxic to L929 cell line while toxic to PC3 and MCF7 cancer cells. Cellular uptake of CRC-FNPs studied using L929, MCF-7 and PC3 cells monitored by fluorescent microscopy, demonstrated significant internalization and retention of nanoparticles inside the cells. The preferential accumulation of curcumin within the cancer cells were also confirmed by flowcytometry based uptake studies. The apoptosis assay showed increased apoptosis on MCF-7 compared to L929 cells. The blood compatibility of CRC-FNPs throws light on the fact that it is possible to administer the prepared nanoformulation intravenously. The results indicated that CRC-FNPs could be a promising therapeutic agent for cancer treatment.

Topics: Animals; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Line; Cell Line, Tumor; Curcumin; Drug Delivery Systems; Female; Fibrinogen; Hemolysis; Humans; In Vitro Techniques; Male; Materials Testing; Mice; Nanocapsules; Nanotechnology; Particle Size; Prostatic Neoplasms

To investigate the efficacy of mitomycin C (MMC) in combination with curcumin in suppressing human breast cancer in vitro and in vivo.. Human breast cancer MCF-7 cells were used. Cell viability was measured using MTT assay. The cell cycle phase was detected with flow cytometric analysis. Cell cycle-associated proteins were examined using Western blot analysis. MCF-7 breast cancer xenografts were established to monitor tumor growth and cell cycle-associated protein expression.. Curcumin inhibited MCF-7 breast cancer cell viability in a concentration-dependent manner (IC(50) value=40 μmol/L). Similarly, MMC inhibited the cell viability with an IC(50) value of 5 μmol/L. Combined treatment of MMC and curcumin showed a synergistic antiproliferative effect. In the presence of curcumin (40 μmol/L), the IC(50) value of MMC was reduced to 5 μmol/L. In MCF-7 xenografts, combined administration of curcumin (100 mg/kg) and MMC (1-2 mg/kg) for 4 weeks produced significantly greater inhibition on tumor growth than either treatment alone. The combined treatment resulted in significantly greater G(1) arrest than MMC or curcumin alone. Moreover, the cell cycle arrest was associated with inhibition of cyclin D1, cyclin E, cyclin A, cyclin-dependent kinase 2 (CDK2) and CDK4, along with the induction of the cell cycle inhibitor p21 and p27 both in MCF-7 cells and in MCF-7 xenografts. These proteins were regulated through p38 MAPK pathway.. The results suggest that the combination of MMC and curcumin inhibits MCF-7 cell proliferation and cell cycle progression in vitro and in vivo via the p38 MAPK pathway.

Topics: Animals; Antineoplastic Agents; Breast; Breast Neoplasms; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Curcumin; Cyclin D1; Cyclin E; Cyclin-Dependent Kinase 2; Drug Synergism; Female; Gene Expression Regulation, Neoplastic; Humans; Mice; Mice, Nude; Mitomycin

The cancer stem cell is defined by its capacity to self-renew, the potential to differentiate into all cells of the tumor and the ability to proliferate and drive the expansion of the tumor. Thus, targeting these cells may provide novel anti-cancer treatment strategies. Breast cancer stem cells have been isolated according to surface marker expression, ability to efflux fluorescent dyes, increased activity of aldehyde dehydrogenase or the capacity to form spheres in non-adherent culture conditions. In order to test novel drugs directed towards modulating self-renewal of cancer stem cells, rapid, easy and inexpensive assays must be developed. Using 2 days-post-fertilization (dpf) zebrafish embryos as transplant recipients, we show that cells grown in mammospheres from breast carcinoma cell lines migrate to the tail of the embryo and form masses with a significantly higher frequency than parental monolayer populations. When stem-like self-renewal was targeted in the parental population by the use of the dietary supplement curcumin, cell migration and mass formation were reduced, indicating that these effects were associated with stem-like cell content. This is a proof of principle report that proposes a rapid and inexpensive assay to target in vivo cancer stem-like cells, which may be used to unravel basic cancer stem cell biology and for drug screening.

Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Curcumin; Embryo, Nonmammalian; Female; Humans; Neoplastic Stem Cells; Xenograft Model Antitumor Assays; Zebrafish

Several tumor markers are overexpressed in breast cancer. Chemotherapy in breast cancer fails due to resistance to chemotherapeutic drugs. A phytochemical such as curcumin can be used in a therapeutic modality as it elicits anti-tumor effects.. Action of curcumin on the expression of several tumor markers, such as protein kinase C, telomerase, NF-kappaB and histone deacetylase in MCF-7 (ER positive), MDA-MB-231 (ER negative), MCF- 12F (control) and also in mice mammary tumors were investigated.. Curcumin downregulated the expression of tumor markers both in vitro and in vivo and sensitized tumor cells to the chemotherapeutic drugs cyclophosphamide and paclitaxel.. Curcumin may be of considerable value in synergistic therapy of cancer such that the drug dose level could be minimized reducing the associated toxicity.

Topics: Animals; Antineoplastic Agents; Biomarkers, Tumor; Breast Neoplasms; Cell Line, Tumor; Curcumin; Cyclophosphamide; Down-Regulation; Drug Resistance, Neoplasm; Drug Synergism; Female; Gene Expression Regulation, Neoplastic; Histone Deacetylases; Humans; Mammary Neoplasms, Experimental; Mice; NF-kappa B; Paclitaxel; Protein Kinase C; Telomerase

The emergence of multidrug resistance (MDR) is a big challenge to cancer chemotherapy. Plant-derived agents have great potential to prevent onset or delay progression of the carcinogenic process, and enhance the efficacy of mainstream antitumor agents. In this study, fractionated extracts of Curcuma wenyujin and Chrysanthemum indicum were tested for their potential to modulate the MDR phenotype and function of P-gp in MCF-7/ADR and A549/Taxol cells in vitro. Fractions C. wenyujin C10, E10 from Curcuma wenyujin, and C. indicum E10 from Chrysanthemum indicum, exhibited significant effects in sensitization of these resistant cancer cells at non-toxic concentration to doxorubicin and docetaxel by MTT method. They also increased the intracellular doxorubicin accumulation and retention in MCF-7/ADR cells. In mechanism study, an increase of Rh123 accumulation and a decrease of Rh123 efflux were observed in MCF-7/ADR cells treated with these fractions, indicating a blockage of the activity of P-gp. Furthermore, C. wenyujin C10 had the ability to down-regulate the expression of P-gp. All these fractions could enhance the apoptosis induced by doxorubicin in MCF-7/ADR cells, and restore the effect of docetaxel on the induction of G2/M arrest in A549/Taxol cells. C. wenyujin C10 and E10 also owned the ability to induce S phase arrest. These results showed the therapeutic value of the three fractions as potential MDR-reversing agents and warranted further investigations.

Topics: Antineoplastic Agents; Apoptosis; ATP Binding Cassette Transporter, Subfamily B, Member 1; Breast Neoplasms; Cell Division; Cell Survival; Chrysanthemum; Curcuma; Doxorubicin; Drug Interactions; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; G2 Phase; Humans; Lung Neoplasms; Medicine, Chinese Traditional; Paclitaxel; Phytotherapy; Plant Extracts

Curcuma phaeocaulis Valeton is a commonly prescribed Chinese medical herb for tumor therapy. In this study, an extract of Curcuma phaeocaulis Valeton referred as Cpv was prepared and its anti-tumor effect was evaluated with MCF-7 and MDA-MB-231 cells. Curcuma phaeocaulis Valeton power was extracted with ethanol and the main components of the extract (Cpv) were analyzed with HPLC. The effect of Cpv on MCF-7 cells proliferation, intracellular reactive oxygen species (ROS) formation, mitochondrial membrane potential (ΔΨm), apoptosis, apoptotic related proteins, MDA-MB-231 cell migration, and integrins expression were determined. Furthermore, the effect of Cpv on some key signal transduction molecules was also investigated. Furanodienone, germacrone and furanodiene were identified as the main components of Cpv. Cpv treatment significantly inhibited cell proliferation, increased LDH release, induced intracellular ROS formation, and decreased ΔΨm in a dose-dependent manner in MCF-7 cells. Cpv induced apoptosis without affecting cell migration. Cpv increased protein expression of Bax, PARP, cleaved PARP, caspase-3, 7, JNK1, p-p42/44MAPK, NF-κB, IKKα, IKKβ, decreased protein expression of Bcl-2, Bcl-xL, Bim, Bik, Bad, integrin β5, p42/44MAPK without affecting integrin α5, β1, and p38MAPK protein expression. We concluded that Cpv inhibited MCF-7 cells proliferation by inducing apoptosis mediated by increasing ROS formation, decreasing ΔΨm, regulating Bcl-2 family proteins expression, and activating caspases. Cpv treatment also modulated several signaling transduction pathways. These results might provide some molecular basis for the anti-tumor activity of Curcuma phaeocaulis Valeton.

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Caspases; Cell Line, Tumor; Cell Movement; Cell Proliferation; Chromatography, High Pressure Liquid; Curcuma; DNA Fragmentation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Ethanol; Female; Humans; Lactate Dehydrogenases; Membrane Potential, Mitochondrial; Plant Extracts; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species; Signal Transduction

Demethoxycurcumin (DMC) is one of the main active compounds of curcuminoids found in turmeric powder, which is used as a spice in Asian cooking and traditional medicine. Recent studies reveal that DMC has several biological activities including anti-inflammation and anti-cancer activities. However, the molecular mechanism by which DMC has anti-metastasis activity in breast cancer cells remains poorly understood. Here, we report for the first time that DMC inhibited adhesion, migration and invasion of MDA-MB-231 human breast cancer cells. For cancer cell migration and invasion, extracellular matrix (ECM) degradation processes are required. MDA-MB-231 cells treated with DMC had decreased levels of ECM degradation-associated proteins including matrix metalloproteinase-9 (MMP-9), membrane type-1 matrix metalloproteinase (MT1-MMP), urokinase plasminogen activator (uPA) and uPA receptor (uPAR), while the level of uPA inhibitor (PAI-1) was up-regulated. Moreover, DMC also reduced the expression of intercellular adhesion molecule-1 (ICAM-1) and chemokine receptor 4, (CXCR4), which is involved in modulation of the tumor metastasis process. We also found that DMC treatment inhibited the DNA binding activity of nuclear factor-kappa B (NF-kappaB), which is known to mediate the expression of MMPs, uPA, uPAR, ICAM-1, and CXCR4. These findings strongly suggest that the mechanism of DMC-mediated anti-invasive activity involves modulation of the expression of invasion-associated proteins, possibly by targeting NF-kappaB in MDA-MB-231 cells.

Topics: Animals; Breast Neoplasms; Cell Adhesion; Cell Line, Tumor; Cell Movement; Curcumin; Diarylheptanoids; DNA; Extracellular Matrix; Gene Expression Regulation, Neoplastic; Humans; Intercellular Adhesion Molecule-1; Neoplasm Invasiveness; Neoplasm Metastasis; NF-kappa B; Receptors, CXCR4

The cancer stem cell hypothesis asserts that malignancies arise in tissue stem and/or progenitor cells through the dysregulation or acquisition of self-renewal. In order to determine whether the dietary polyphenols, curcumin, and piperine are able to modulate the self-renewal of normal and malignant breast stem cells, we examined the effects of these compounds on mammosphere formation, expression of the breast stem cell marker aldehyde dehydrogenase (ALDH), and Wnt signaling. Mammosphere formation assays were performed after curcumin, piperine, and control treatment in unsorted normal breast epithelial cells and normal stem and early progenitor cells, selected by ALDH positivity. Wnt signaling was examined using a Topflash assay. Both curcumin and piperine inhibited mammosphere formation, serial passaging, and percent of ALDH+ cells by 50% at 5 microM and completely at 10 microM concentration in normal and malignant breast cells. There was no effect on cellular differentiation. Wnt signaling was inhibited by both curcumin and piperine by 50% at 5 microM and completely at 10 microM. Curcumin and piperine separately, and in combination, inhibit breast stem cell self-renewal but do not cause toxicity to differentiated cells. These compounds could be potential cancer preventive agents. Mammosphere formation assays may be a quantifiable biomarker to assess cancer preventive agent efficacy and Wnt signaling assessment can be a mechanistic biomarker for use in human clinical trials.

Topics: Aldehyde Dehydrogenase; Alkaloids; Antineoplastic Combined Chemotherapy Protocols; Benzodioxoles; Breast; Breast Neoplasms; Cell Differentiation; Cell Proliferation; Cells, Cultured; Curcumin; Female; Humans; Immunoenzyme Techniques; Neoplastic Stem Cells; Piperidines; Polyunsaturated Alkamides; Signal Transduction; Wnt Proteins

The medicinal properties of curcumin are well documented in Indian and Chinese systems of medicine, which refer to its wide use in the treatment of some diseases. It has shown to have anti-carcinogenic properties and is known to prevent tumor development in some cancers. In our study, we confirmed that the expression of miR-15a and miR-16 was upregulated and that of Bcl-2 was downregulated in curcumin-treated MCF-7 cells. Silencing miR-15a and miR-16 by specific inhibitors restored the expression of Bcl-2. Thus, we concluded that curcumin can reduce the expression of Bcl-2 by upregulating the expression of miR-15a and miR-16 in MCF-7 cells.

Topics: Adenocarcinoma; Antineoplastic Agents; Blotting, Western; Breast Neoplasms; Curcumin; Female; Humans; MicroRNAs; Proto-Oncogene Proteins c-bcl-2; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Cells, Cultured; Up-Regulation

In breast cancer, maspin, a serine protease inhibitor, can suppress tumor growth and metastasis in vivo and tumor cell motility and invasion in vitro. The clinical significance of maspin expression in breast cancer, especially in the sequence of ductal carcinoma in situ (DCIS)-invasive cancer-lymph node metastasis is well known in the Western countries, but its status in the rapidly increasing breast cancers in India remains unknown. The present study was designed to determine the clinical significance of maspin expression in invasive ductal carcinomas of breast (IDCs) in North Indian population and modulation of its expression by curcumin. Immunohistochemical analysis of maspin showed loss or reduced cytoplasmic expression in 36 of 59 (61%) tumors. Furthermore, breast cancer cells (MCF-7 (wild type p53) and MDA-MB-231 (mutant p53)) were treated with curcumin and the effect on expression of maspin gene at transcription and translation levels was analyzed by RT-PCR, immunofluorescence and Western blotting. Maspin expression was also correlated with p53 and Bcl-2 levels. Curcumin inhibited cell growth, induced apoptosis and upregulated maspin gene expression in MCF-7 cells and these findings were further correlated with the upregulation of p53 protein and downregulation of Bcl-2, suggesting maspin mediated apoptosis in MCF-7 cells. To our knowledge this is the first report showing the upregulation of maspin expression by curcumin in breast cancer cells and taken together with the clinical data suggests a potential therapeutic role for curcumin in inducing maspin mediated inhibition of invasion of breast carcinoma cells.

Topics: Antineoplastic Agents; Breast Neoplasms; Carcinoma, Ductal, Breast; Curcumin; Female; Humans; Proto-Oncogene Proteins c-bcl-2; Serpins; Tumor Cells, Cultured; Tumor Suppressor Protein p53; Up-Regulation

Curcumin is considered a pharmacologically safe agent that may be useful in cancer chemoprevention and therapy. Here, we show for the first time that curcumin effectively induces paraptosis in malignant breast cancer cell lines, including MDA-MB-435S, MDA-MB-231, and Hs578T cells, by promoting vacuolation that results from swelling and fusion of mitochondria and/or the endoplasmic reticulum (ER). Inhibition of protein synthesis by cycloheximide blocked curcumin-induced vacuolation and subsequent cell death, indicating that protein synthesis is required for this process. The levels of AIP-1/Alix protein, a known inhibitor protein of paraptosis, were progressively downregulated in curcumin-treated malignant breast cancer cells, and AIP-1/Alix overexpression attenuated curcumin-induced death in these cells. ERK2 and JNK activation were positively associated with curcumin-induced cell death. Mitochondrial superoxide was shown to act as a critical early signal in curcumin-induced paraptosis, whereas proteasomal dysfunction was mainly responsible for the paraptotic changes associated with ER dilation. Notably, curcumin-induced paraptotic events were not observed in normal breast cells, including mammary epithelial cells and MCF-10A cells. Taken together, our findings on curcumin-induced paraptosis may provide novel insights into the mechanisms underlying the selective anti-cancer effects of curcumin against malignant cancer cells.

Topics: Breast Neoplasms; Cell Death; Cell Line, Tumor; Curcumin; Cycloheximide; Endoplasmic Reticulum; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Intracellular Signaling Peptides and Proteins; Mammary Glands, Human; MAP Kinase Kinase 4; Membrane Fusion; Mitochondrial Swelling; Proteasome Endopeptidase Complex; Superoxides; Vacuoles

The constitutive activation of signal transducer and activator of transcription 3 (STAT3) is frequently detected in most types of human cancer where it plays important roles in survival, drug resistance, angiogenesis, and other functions. Targeting constitutive STAT3 signaling is thus an attractive therapeutic approach for these cancers. We have recently developed novel small-molecule STAT3 inhibitors, known as FLLL31 and FLLL32, which are derived from curcumin (the primary bioactive compound of turmeric). These compounds are designed to bind selectively to Janus kinase 2 and the STAT3 Src homology-2 domain, which serve crucial roles in STAT3 dimerization and signal transduction. Here we show that FLLL31 and FLLL32 are effective inhibitors of STAT3 phosphorylation, DNA-binding activity, and transactivation in vitro, leading to the impediment of multiple oncogenic processes and the induction of apoptosis in pancreatic and breast cancer cell lines. FLLL31 and FLLL32 also inhibit colony formation in soft agar and cell invasion and exhibit synergy with the anticancer drug doxorubicin against breast cancer cells. In addition, we show that FLLL32 can inhibit the induction of STAT3 phosphorylation by IFNalpha and interleukin-6 in breast cancer cells. We also show that administration of FLLL32 can inhibit tumor growth and vascularity in chicken embryo xenografts as well as substantially reduce tumor volumes in mouse xenografts. Our findings highlight the potential of these new compounds and their efficacy in targeting pancreatic and breast cancers that exhibit constitutive STAT3 signaling.

Topics: Animals; Breast Neoplasms; Cell Growth Processes; Cell Line, Tumor; Chick Embryo; Curcumin; Down-Regulation; Female; Humans; Janus Kinase 2; Mice; Mice, Nude; Models, Molecular; Pancreatic Neoplasms; Phosphorylation; src Homology Domains; STAT3 Transcription Factor; Xenograft Model Antitumor Assays

Curcumin, a natural compound isolated from turmeric, may inhibit cell proliferation in various tumor cells through a mechanism that is not fully understood. The enhancer of zeste homolog 2 (EZH2) gene is overexpressed in human breast cancers with poor prognosis. In this study, we observed a dose- and time-dependent down-regulation of expression of EZH2 by curcumin that correlates with decreased proliferation in the MDA-MB-435 breast cancer cell line. The curcumin treatment resulted in an accumulation of cells in the G(1) phase of the cell cycle. Further investigation revealed that curcumin-induced down-regulation of EZH2 through stimulation of three major members of the mitogen-activated protein kinase (MAPK) pathway: c-Jun NH2-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and p38 kinase. These data suggest that an underlying mechanism of the MAPK pathway mediates the down-regulation of EZH2, thus contributing to the anti-proliferative effects of curcumin against breast cancer.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Curcumin; DNA-Binding Proteins; Down-Regulation; Enhancer of Zeste Homolog 2 Protein; Extracellular Signal-Regulated MAP Kinases; Female; Gene Expression Regulation, Neoplastic; Humans; JNK Mitogen-Activated Protein Kinases; MAP Kinase Signaling System; p38 Mitogen-Activated Protein Kinases; Polycomb Repressive Complex 2; Transcription Factors

Poor oral bioavailability limits the use of curcumin and other dietary polyphenols in the prevention and treatment of cancer. Minimally invasive strategies that can provide effective and sustained tissue concentrations of these agents will be highly valuable tools in the fight against cancer. The objective of this study was to investigate the use of an injectable sustained release microparticle formulation of curcumin as a novel approach to breast cancer chemoprevention. A biodegradable and biocompatible polymer, poly(d,l-lactide-co-glycolide), was used to fabricate curcumin microparticles. When injected s.c. in mice, a single dose of microparticles sustained curcumin levels in the blood and other tissues for nearly a month. Curcumin levels in the lungs and brain, frequent sites of breast cancer metastases, were 10- to 30-fold higher than that in the blood. Further, curcumin microparticles showed marked anticancer efficacy in nude mice bearing MDA-MB-231 xenografts compared with other controls. Repeated systemic injections of curcumin were not effective in inhibiting tumor growth. Treatment with curcumin microparticles resulted in diminished vascular endothelial growth factor expression and poorly developed tumor microvessels, indicating a significant effect on tumor angiogenesis. These results suggest that sustained delivery of chemopreventives such as curcumin using polymeric microparticles is a promising new approach to cancer chemoprevention and therapy.

Topics: Animals; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Growth Processes; Cell Line, Tumor; Curcumin; Cyclin D1; Cyclooxygenase 2; Delayed-Action Preparations; Down-Regulation; Female; Humans; Lactic Acid; Matrix Metalloproteinase 9; Mice; Mice, Inbred BALB C; Neovascularization, Pathologic; Particle Size; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Random Allocation; Vascular Endothelial Growth Factor A

Curcumin has been shown highly cytotoxic towards various cancer cell lines, but its water-insolubility and instability make its bioavailability exceedingly low and thus it generally demonstrates low anticancer activity in in vivo tests. Herein, we report a novel type of polymer-drug conjugates--the high molecular weight curcumin polymers (polycurcumins) made by condensation polymerization of curcumin. The polycurcumins as backbone-type conjugates have advantages of high drug loading efficiency, fixed drug loading contents, stabilized curcumin in their backbones, and tailored water-solubility. The polycurcumins may have many potential applications and their antitumor activities are investigated in this work. The polycurcumins are cytotoxic to cancer cells, but a polyacetal-based polycurcumin (PCurc 8) is highly cytotoxic to SKOV-3, OVCAR-3 ovarian cancers, and MCF-7 breast cancer cell lines. It can be quickly taken up by cancer cells into their lysosomes, where PCurc 8 hydrolyzes and releases active curcumin. It arrests SKOV-3 cell cycle at G(0)/G(1) phase in vitro and induces cell apoptosis partially through the caspase-3 dependent pathway. In vivo, intravenously (i.v.) injected PCurc 8 shows remarkable antitumor activity in SKOV-3 intraperitoneal (i.p.) xenograft tumor model.

Topics: Animals; Antineoplastic Agents; Apoptosis; Blotting, Western; Breast Neoplasms; Caspase 3; Curcumin; Female; Fluorescent Antibody Technique; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Ovarian Neoplasms; Polymers; Xenograft Model Antitumor Assays

In this study, curcumin, a potential anticancer agent, was found to dampen the dynamic instability of individual microtubules in living MCF-7 cells. It strongly reduced the rate and extent of shortening states, and modestly reduced the rate and extent of growing states. In addition, curcumin decreased the fraction of time microtubules spent in the growing state and strongly increased the time microtubules spent in the pause state. Brief treatment with curcumin depolymerized mitotic microtubules, perturbed microtubule-kinetochore attachment and disturbed the mitotic spindle structure. Curcumin also perturbed the localization of the kinesin protein Eg5 and induced monopolar spindle formation. Further, curcumin increased the accumulation of Mad2 and BubR1 at the kinetochores, indicating that it activated the mitotic checkpoint. In addition, curcumin treatment increased the metaphase/anaphase ratio, indicating that it can delay mitotic progression from the metaphase to anaphase. We provide evidence suggesting that the affected cells underwent apoptosis via the p53-dependent apoptotic pathway. The results support the idea that kinetic stabilization of microtubule dynamics assists in the nuclear translocation of p53. Curcumin exerted additive effects when combined with vinblastine, a microtubule depolymerizing drug, whereas the combination of curcumin with paclitaxel, a microtubule-stabilizing drug, produced an antagonistic effect on the inhibition of MCF-7 cell proliferation. The results together suggested that curcumin inhibited MCF-7 cell proliferation by inhibiting the assembly dynamics of microtubules.

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Curcumin; Female; Humans; Kinesins; Microtubules; Mitosis; Protein Stability; Protein Transport; Spindle Apparatus; Time Factors; Tubulin

Matrix metalloproteinase-3 (MMP-3) is a key enzyme with important implications in the invasion and metastasis of breast cancer cells. Curcumin (Cur), demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC) are major forms of curcuminoids found in turmeric powder with reported anticancer activity. This study focuses on the comparative effect of Cur, DMC and BDMC on the modulation of MMP-3 activity and its secretion in MDA-MB-231 breast cancer cells. MMP-3 levels were determined by casein zymography, ELISA and western blotting. Analysis of MMP-3 expression by casein zymography revealed high expression in MDA-MB-231 invasive breast carcinoma cells, but not in MCF-7 non-invasive breast cancer cells. ELISA assays showed MMP-3 levels were significantly decreased in all curcuminoid treatments. Using zymography, treatment with non-toxic doses revealed that every curcuminoid compound except Cur reduced MMP-3 levels. Moreover, the result from western blot analysis confirmed that only DMC and BDMC reduced MMP-3 secretion in MDA-MB-231 cells, but Cur did not have any effect. MMP-3 activity revealed that none of the curcuminoids showed significant effects. However, treatment of the cells with Cur, DMC and BDMC exhibited a significant inhibition of cell invasion and motility with DMC and BDMC being more potent. These results suggest that Cur, DMC, and BDMC may be used as MMP-3 inhibitors to modulate MMP-3 expression.

Topics: Animals; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cell Line, Tumor; Curcuma; Curcumin; Diarylheptanoids; Dose-Response Relationship, Drug; Female; Humans; Matrix Metalloproteinase 3; Matrix Metalloproteinase Inhibitors; Mice; Neoplasm Staging; NIH 3T3 Cells

A series of 18 heterocyclic cyclohexanone analogues of curcumin have been synthesised and screened for their activity in both adherent and non-adherent cancer cell models. Cytotoxicity towards MBA-MB-231 breast cancer cells, as well as ability to inhibit NF-kappaB transactivation in non-adherent K562 leukemia cells were investigated. Three of these analogues 3,5-bis(pyridine-4-yl)-1-methylpiperidin-4-one B1, 3,5-bis(3,4,5-trimethoxybenzylidene)-1-methylpiperidin-4-one B10, and 8-methyl-2,4-bis((pyridine-4-yl)methylene)-8-aza-bicyclo[3.2.1]octan-3-one C1 showed potent cytotoxicity towards MBA-MB-231, MDA-MB-468, and SkBr3 cell lines with EC50 values below 1 microM and inhibition of NF-kappaB activation below 7.5 microM. The lead drug candidate, B10, was also able to cause 43% of MDA-MB-231 cells to undergo apoptosis after 18 h. This level of activity warrants further investigation for the treatment of ER-negative breast cancer and/or chronic myelogenous leukemia as prototypical cellular models for solid and liquid tumors.

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Curcumin; Cyclohexanones; Female; Heterocyclic Compounds; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; NF-kappa B; Structure-Activity Relationship

Since curcumin, a polyphenol extracted from the rhizomes of Curcuma longa L. (Zingiberaceae), has been proposed for breast cancer chemoprevention, the aim of the present work was to determine if it had anti-tumour effects on mammary cells which are resistant to oxidative damage. ZR-75-1 cells were treated with curcumin and copper(II) sulphate in order to evaluate cell death and gamma-glutamyltranspeptidase (GGTP) activity. Curcumin was cytotoxic in a dose-dependent manner (loss of viability with lactate-dehydrogenase release) with apoptotic effects on ZR-75-1 cells. Also, curcumin displayed an antioxidant effect only on the copper-oxidized cells. The GGTP activity was decreased in a dose-dependent manner by curcumin, with the changes in this parameter accounting for neoplastic inhibition (direct relation between the enzyme activity and cellular viability). Summing up, our results suggest that curcumin induced apoptosis in ZR-75-1 with an antioxidant activity performed on those treated with copper(II) sulphate, which should be explored more thoroughly with the involvement of the GGTP enzyme activity as biomarker of their malignancy.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Curcumin; Enzyme Inhibitors; Female; Free Radicals; gamma-Glutamyltransferase; Humans; Oxidation-Reduction

The natural product curcumin has long been recognized for its medicinal properties and is utilized for the treatment of many diseases. However, it remains unknown whether this activity is based on its presumably promiscuous scaffold, or if it results from the Michael acceptor properties of the alpha,beta-unsaturated 1,3-diketone moiety central to its structure. To probe this issue, electron-rich pyrazole and isoxazole analogues were prepared and evaluated against two breast cancer cell lines, which resulted in the identification of several compounds that exhibit low micromolar to mid nanomolar anti-proliferative activity. A conjugate addition study was also performed to compare the relative electrophilicity of the diketone, pyrazole and isoxazole analogues.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Curcumin; Electrons; Female; Humans; Isoxazoles; Pyrazoles; Structure-Activity Relationship

Curcumin has been reported to have the potential to prevent obesity as well as cancers. The downstream targets regulated by AMP-activated protein kinase (AMPK) for inhibiting adipocyte differentiation or cancer cell proliferation of curcumin were investigated. The activation of AMPK by curcumin was crucial for the inhibition of differentiation or growth in both adipocytes and cancer cells. Stimulation of AMPK by curcumin resulted in the down-regulation of PPAR (peroxisome proliferator-activated receptor)-gamma in 3T3-L1 adipocytes and the decrease in COX-2 in MCF-7 cells. Application of a synthetic AMPK activator also supported the evidence that AMPK acts as an upstream signal of PPAR-gamma in 3T3-L1 adipocytes. In cancer cells, AMPK was found to act as a regulator of ERK1/2, p38, and COX-2. Regulation of AMPK and its downstream targets such as PPAR-gamma, Mapkinases, and COX-2 by curcumin appears to be important in controlling adipocytes and cancerous cells.

Topics: 3T3-L1 Cells; Adipocytes; AMP-Activated Protein Kinases; Animals; Apoptosis; Breast Neoplasms; Cell Differentiation; Cell Division; Cell Line, Tumor; Curcumin; Cyclooxygenase 2; Enzyme Activation; HT29 Cells; Humans; Mice; PPAR gamma

We examine the possible evidence that the phytochemical curcumin may overcome resistance to hormonal and cytotoxic agents in breast cancer. We present our observations on MCF-7R, a multidrug-resistant (MDR) variant of the MCF-7 breast cancer cell line. In contrast to MCF-7, MCF-7R lacks aromatase and estrogen receptor alpha (ERalpha) and overexpresses the multidrug transporter ABCB1 and the products of different genes implicated in cell proliferation and survival, like c-IAP-1, NAIP, survivin, and COX-2. Nevertheless, in cytotoxicity and cell death induction assays, we found that the antitumor activity of curcumin is substantial both in MCF-7 and in MCF-7R. We elaborated the diketone system of curcumin into different analogues; the benzyloxime and the isoxazole and pyrazole heterocycles showed remarkable increases in the antitumor potency both in the parental and in the MDR MCF-7 cells. Furthermore, curcumin or, more potently, the isoxazole analogue, produced early reductions in the amounts of relevant gene transcripts that were diverse (i.e., they were relative to Bcl-2 and Bcl-X(L) in MCF-7 and the inhibitory of apoptosis proteins and COX-2 in MCF-7R) in the two cell lines. Thus, the two compounds exhibited the remarkable property of being able to modify their molecular activities according to the distinct characteristics of the parental and MDR cells. We discuss also how curcumin may (1) exert antitumor effects in breast cancer through ER-dependent and ER-independent mechanisms; and (2) act as a drug transporter-mediated MDR reversal agent. Overall, the structure of curcumin may represent the basis for the development of new, effective anticancer agents in hormone-independent MDR breast cancer.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Curcumin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Gene Expression Profiling; Humans

Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione), is extracted from the plant Curcuma longa. It has cytotoxic effects and induces apoptosis in many human cancer cells but the molecular mechanisms are not fully understood. In the present study, we evaluated the effects of curcumin on human breast cancer MDA-MB-231 cells. The cytotoxic effects of curcumin on MDA-MB-231 cells were measured by MTT assay. The percentages of cell cycle were determined by flow cytometry. The protein expressions of p21, 53, Bax and Bcl-2 were examined by Western blotting. The results show that curcumin inhibits the proliferation of MDA-MB-231 cells and induces G2/M arrest in a dose-dependent manner. Curcumin increased the protein expressions of p21 and Bax, but decreased the protein expression of p53 and Bcl-2 in MDA-MB-231 cells. Our results show that one molecular mechanism of curcumin inhibits the proliferation of MDA-MB-231 cells either through up-regulating p21 expression and then inducing apoptosis, or through up-regulating the Bax to Bcl-2 ratio and then inducing apoptosis. Our results also show that curcumin inhibits the migratory activity of MDA-MB-231 cells through down-regulating the protein expression of NF-kappaBp65. Accordingly, the therapeutic potential of curcumin for breast cancer deserves further study.

Topics: Antineoplastic Agents; bcl-2-Associated X Protein; Blotting, Western; Breast Neoplasms; Cell Division; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Curcumin; Dose-Response Relationship, Drug; Flow Cytometry; G2 Phase; Growth Inhibitors; Humans; Models, Biological; Proto-Oncogene Proteins c-bcl-2; Transcription Factor RelA

Biologically derived nanoparticles (<100 nm) were fabricated for local and sustained therapeutic curcumin delivery to cancer cells. Silk fibroin (SF) and chitosan (CS) polymers were blended noncovalently to encapsulate curcumin in various proportions of SF and CS (75:25, 50:50, and 25:75 SF:CS) or pure SF at two concentrations (0.1% w/v and 10% w/v) using the devised capillary-microdot technique. Curcumin-polymer conjugates were frozen, lyophilized, crystallized, suspended in phosphate-buffered saline for characterization, and tested for efficacy against breast cancer cells. All nanoparticle formulations except 0.1% w/v 50:50 SFCS were less than 100 nm in size as determined with the transmission electron microscopy. The entrapment and release of curcumin over eight days was highest for SF-derived nanoparticles as compared to all SFCS blends. The uptake and efficacy of SF-coated curcumin was significantly higher (p < 0.001) than SFCS-coated curcumin in both low and high Her2/neu expressing breast cancer cells. Interestingly, the uptake of curcumin was highest for the high Her2/neu expressing breast cancer cells when delivered with a 10% w/v SF coating as compared to other formulations. In conclusion, SF-derived curcumin nanoparticles show higher efficacy against breast cancer cells and have the potential to treat in vivo breast tumors by local, sustained, and long-term therapeutic delivery as a biodegradable system.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Curcumin; Diffusion; Drug Carriers; Fibroins; Humans; Nanoparticles

Curcumin, an active constituent of turmeric, has been shown to possess inhibitory effect of cell proliferation and induction of apoptosis towards a board range of tumors. Cell inhibition activities of curcumin are behaved differently in various cell types. To investigate the mechanism basis for the cell inhibition of curcumin on breast cancer cell lines, we examine curcumin effect on NFkappaB, cell cycle regulatory proteins and matrix metalloproteinases (MMPs) in two breast cancer cell lines (MDA-MB-231 and BT-483). Cell proliferation was performed by water soluble tetrazolium WST-1 assay. The effect of curcumin's on the activity of matrix metalloproteinase-1, 3, 9 were analyzed by RT-PCR. Cell cycle regulatory protein including cyclin D1, CDK4 and p21 were examined by immunochemistry. The expressions of NFkappaB in breast cancer cells treated with curcumin were studied by immunochemistry and western blot. The results from WST-1 cell proliferation assay showed that curcumin exhibited the anti-proliferation effect on MDA-MB-231 and BT-483 cells in a time- and dose-dependent manner. In response to the treatment, while, the expression of cyclin D1 had declined in MDA-MB-231 and the expression of CDK4 in BT-483 had declined. MMP1 mRNA expression in BT-483 and MDA-MB-231 had significantly decreased in curcumin treatment group compared with control group. Our finding extrapolates the antitumor activity of curcumin in mediating the breast cancer cell proliferative rate and invasion by down-regulating the NFkappaB inducing genes.

Topics: Adenocarcinoma; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Curcuma; Curcumin; Cyclin D; Cyclin-Dependent Kinase 4; Down-Regulation; Drug Screening Assays, Antitumor; Female; Humans; Immunohistochemistry; Matrix Metalloproteinase 1; NF-kappa B; p21-Activated Kinases; Phytotherapy; Plant Extracts

Curcumin, the active component of turmeric, has been shown to protect against carcinogenesis and prevent tumor development in cancer. To enhance its potency, we tested the efficacy of synthetic curcumin analogues, known as FLLL11 and FLLL12, in cancer cells. We examined the impact of FLLL11 and FLLL12 on cell viability in eight different breast and prostate cancer cell lines. FLLL11 and FLLL12 (IC(50) values 0.3-5.7 and 0.3-3.8 micromol/L, respectively) were substantially more potent than curcumin (IC(50) values between 14.4-50 micromol/L). FLLL11 and FLLL12 were also found to inhibit AKT phosphorylation and downregulate the expression of HER2/neu. In addition, we demonstrate for the first time that FLLL11 and FLLL12 inhibit phosphorylation of signal transducer and activator of transcription (STAT) 3, an oncogene frequently found to be persistently active in many cancer types. The inhibition of STAT3 signaling was confirmed by the inhibition of STAT3 DNA binding and STAT3 transcriptional activity. Furthermore, FLLL11 and FLLL12 were more effective than curcumin in inhibiting cell migration and colony formation in soft agar as well as inducing apoptosis in cancer cells. These results indicate that FLLL11 and FLLL12 exhibit more potent activities than curcumin on the inhibition of STAT3, AKT, and HER-2/neu, as well as inhibit cancer cell growth and migration, and may thus have translational potential as chemopreventive or therapeutic agents for breast and prostate cancers.

Topics: Blotting, Western; Breast Neoplasms; Cell Adhesion; Cell Movement; Cell Proliferation; Colony-Forming Units Assay; Curcumin; Female; Growth Inhibitors; Humans; Male; Phosphorylation; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; STAT3 Transcription Factor

Abnormal activation of the Wnt/beta-catenin signaling pathway and subsequent upregulation of beta-catenin driven downstream targets-c-Myc and cyclin D1 is associated with development of breast cancer. The objective of our study was to determine if curcumin could modulate the key elements of Wnt pathway in breast cancer cells; an effect that might underscore its usefulness for chemoprevention/treatment of this malignancy. Curcumin showed a cytotoxic effect on MCF-7 cells with 50% inhibitory concentration (IC(50)) of 35microM; while IC(50) for MDA-MB-231 cells was 30microM. Treatment with low cytostatic dose of 20microM curcumin showed G(2)/M arrest in both breast cancer cells. The effect of curcumin (20microM) treatment on expression of Wnt/beta-catenin pathway components in breast cancer cells (MCF-7 and MDA-MB-231) was analyzed by immunofluorescence and Western blotting. Curcumin was found to effectively inhibit the expression of several Wnt/beta-catenin pathway components-disheveled, beta-catenin, cyclin D1 and slug in both MCF-7 and MDA-MB-231. Immunofluorescence analysis showed that curcumin markedly reduced the nuclear expression of disheveled and beta-catenin proteins. Further, the protein levels of the positively regulated beta-catenin targets-cyclin D1 and slug, were downregulated by curcumin treatment. The expression levels of two integral proteins of Wnt signaling, GSK3beta and E-cadherin were also altered by curcumin treatment. In conclusion, our data demonstrated that the efficacy of curcumin in inhibition of cell proliferation and induction of apoptosis might occur through modulation of beta-catenin pathway in human breast cancer cells.

Topics: beta Catenin; Blotting, Western; Breast Neoplasms; Cell Cycle; Cell Division; Cell Line, Tumor; Curcumin; Female; Flow Cytometry; Fluorescent Antibody Technique; Humans; Signal Transduction; Wnt Proteins

Curcumin has numerous anti-carcinogenic properties, but low bioavailability prevents its use in chemotherapeutic applications. One strategy for circumventing this problem has been the creation of synthetic analogues. We tested the efficacy of an analogue known as GO-Y030 in human breast and pancreatic cancer cells. We compared the impact of curcumin and GO-Y030 on the breast cancer cell line MDA-MB-231 and pancreatic cancer cell lines, PANC-1, HPAC and BXPC-3. Both compounds reduced cell viability and induced apoptosis, but GO-Y030 was substantially more potent. We also demonstrated that GO-Y030 was capable of interfering with STAT3, a persistently activated transcription factor in many cancer types. GO-Y030 inhibited STAT3 phosphorylation and transcriptional activity whereas comparable dosages of curcumin had little or no effect. These results indicate that GO-Y030 is a potent inhibitor of cell viability and STAT3 activation, and may thus have potential as a therapeutic agent for cancers expressing high levels of activated STAT3.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Breast Neoplasms; Cell Adhesion; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; Dose-Response Relationship, Drug; Female; Humans; Inhibitory Concentration 50; Pancreatic Neoplasms; Phosphorylation; STAT3 Transcription Factor; Transcription, Genetic; Transfection

To observe the effect of curcumin on protein kinases on cell signal pathway in breast cancer cell MCF-7.. The suppressive effect of curcumin on MCF-7 cell proliferation as different concentration and at different time points were observed by MTT assay; The activity of p-ERK, p-NF-kappaB, p-p38 and p-JNK were observed by western blot.. The suppressive effect of curcumin was shown as a dose dependent and a time dependent manner,and the IC50 was 22.48 micromol/L 40 micromol/L curcumin inhibited the expression of p-ERK, p-NF-kappaB and p-p38, but not p-JNK.. Curcumin can inhibit MCF-7 cell's proliferation, and its mechanism may be related to the activities of protein kinases on cell signal pathway.

Topics: Antineoplastic Agents, Phytogenic; Blotting, Western; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcuma; Curcumin; Dose-Response Relationship, Drug; Enzyme Inhibitors; Extracellular Signal-Regulated MAP Kinases; Female; Humans; JNK Mitogen-Activated Protein Kinases; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Protein-Tyrosine Kinases; Signal Transduction

Phosphatase of regenerating liver-3 (PRL-3) has been suggested as a potential target for anticancer drugs based on its involvement in tumor metastasis. However, little is known about a small-molecule inhibitor against PRL-3. In this study, we report that curcumin, the component of the spice turmeric, shows its antitumor effect by selectively down-regulating the expression of PRL-3 but not its family members PRL-1 and -2 in a p53-independent way. Curcumin inhibited the phosphorylation of Src and stat3 partly through PRL-3 down-regulation. Cells with PRL-3 stably knocked down show less sensitivity to curcumin treatment, which reveals that PRL-3 is the much further upstream target of curcumin. Curcumin treatment also remarkably prevented B16BL6 from invading the draining lymph nodes in the spontaneous metastatic tumor model, which is probably of relevance to PRL-3 down-regulation. Our results reveal a novel capacity of curcumin to down-regulate oncogene PRL-3, raising its possibility in therapeutic regimen against malignant tumor.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Curcumin; Down-Regulation; Female; Gene Expression Regulation, Neoplastic; Humans; Immediate-Early Proteins; Male; Melanoma; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Neoplasms, Experimental; Prostatic Neoplasms; Protein Tyrosine Phosphatases; Proto-Oncogene Proteins pp60(c-src); Reverse Transcriptase Polymerase Chain Reaction; STAT3 Transcription Factor; Transcription, Genetic; Tumor Suppressor Protein p53

A series of novel curcumin analogs, symmetrical dienones, were previously shown to possess cytotoxic, anti-angiogenic and anti-tumor activities. Analogs 1 (EF24) and 2 (EF31) share the dienone scaffold and serve as Michael acceptors. We propose that the anti-cancer effects of 1 and 2 are mediated in part by redox-mediated induction of apoptosis. In order to support this concept, 1 and 2 were treated with L-glutathione (GSH) and cysteine-containing dipeptides under mild conditions to form colorless water-soluble adducts, which were identified by LC/MS. Comparison of the cytotoxic action of 1, 2 and the corresponding conjugates, 1-(GSH)(2) and 2-(GSH)(2), illustrated that the two classes of compounds exhibit essentially identical cell killing capabilities. Compared with the yellow, somewhat light sensitive and nearly water insoluble compounds 1 and 2, the glutathione conjugates represent a promising new series of stable and soluble anti-tumor pro-drugs.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Curcumin; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Oxidation-Reduction; Stereoisomerism

Topics: Breast Neoplasms; Curcumin; Exosomes; Female; Heat-Shock Proteins; Humans; Liver Cirrhosis; Neoplasms; Paracrine Communication

Tissue factor/coagulation factor VII (fVII) complex formation on the surface of cancer cells plays important roles in cancer biology, such as cell migration and invasion, angiogenesis, and antiapoptotic effects. We recently found that various cancer cells ectopically synthesize fVII, resulting in activation of cell motility and invasion. Here, we characterized mechanisms of hepatic and ectopic fVII (FVII) gene expression to identify molecular targets enabling selective inhibition of the ectopic expression. Unlike hepatic expression, hepatocyte nuclear factor-4 binding to the promoter is not required for ectopic FVII expression, although Sp1 binding is essential. Furthermore, we found novel nuclear targets of basal hepatocytic and ectopic FVII expression. Notably, histone acetyltransferases p300 and cyclic AMP-responsive element binding protein-binding protein (CBP) are exclusively recruited to the promoter region of the FVII gene specifically in breast cancer cells. We further show that curcumin, a dietary compound, can selectively inhibit ectopic fVII expression by targeting p300/CBP activity. These results suggest a strategy to inhibit ectopic fVII-induced tumor progression without impairment of the physiologic hemostatic process.

Topics: Acetylation; Animals; Binding Sites; Breast Neoplasms; Cell Line, Tumor; Chromatin; Curcumin; E1A-Associated p300 Protein; Enzyme Inhibitors; Factor VII; Female; Gene Expression Regulation, Neoplastic; Hepatocyte Nuclear Factor 4; Hepatocytes; Histone Acetyltransferases; Humans; Liver; Mice; Neoplasm Proteins; Promoter Regions, Genetic; Protein Binding

Topics: Alkaloids; Anticarcinogenic Agents; Benzodioxoles; Breast; Breast Neoplasms; Clinical Trials as Topic; Curcumin; Diet; Estrogen Antagonists; Humans; Piperidines; Polyunsaturated Alkamides; Stem Cells

Furanodiene is a sesquiterpene extracted from the essential oil of the rhizome of Curcuma wenyujin Y.H. Chen et C. Ling (Wen Ezhu). Furanodiene is the primary component in Wen Ezhu's essential oil, accounting for more than 20% by weight. In vitro, MTT assay was used to compare the inhibitory effects of furanodiene and Wen Ezhu's essential oil on 11 human cancer cell lines. Compared to the essential oil, furanodiene showed stronger growth inhibitions on Hela, Hep-2, HL-60, PC3, SGC-7901 and HT-1080 cells with IC(50) between 0.6-4.8 microg/ml. In vivo, furanodiene was also found to exhibit inhibitory effects on the growth of uterine cervical (U14) and sarcoma 180 (Sl80) tumors in mice. Our data suggests that furanodiene, an active component from the essential oil of Wen Ezhu, possesses efficacy against uterine cervical cancer.

Topics: Adenocarcinoma; Animals; Breast Neoplasms; Carcinoma, Hepatocellular; Cell Division; Curcuma; Drugs, Chinese Herbal; Female; Fibrosarcoma; Furans; HeLa Cells; Heterocyclic Compounds, 2-Ring; HL-60 Cells; Humans; K562 Cells; Leukemia; Liver Neoplasms; Lung Neoplasms; Mice; Mice, Inbred Strains; Organ Size; Sesquiterpenes; Spleen; Thymus Gland; Uterine Cervical Neoplasms; Xenograft Model Antitumor Assays

We have recently shown that macrophage-stimulating protein (MSP) promotes the invasion of recepteur d'origine nantais (RON), a tyrosine kinase receptor-positive MDA-MB-231, MDA-MB-468 breast cancer cells, and also identified the regulatory elements required for RON gene expression. In this report, we have analyzed the efficacy of a chemopreventive agent, curcumin, in blocking RON tyrosine kinase-mediated invasion of breast cancer cells. Reverse transcription-PCR and Western analysis indicated the down-regulation of the RON message and protein, respectively, in MDA-MB-231 and MDA-MB-468 cells. Significantly, curcumin-mediated inhibition of RON expression resulted in the blockade of RON ligand, MSP-induced invasion of breast cancer cells. We have identified two putative nuclear factor-kappaB p65 subunit binding sites on the RON promoter. Using chromatin immunoprecipitation analysis and site-directed mutagenesis of the RON promoter, we have confirmed the binding of p65 to the RON promoter. Our data show that curcumin reduces RON expression by affecting p65 protein expression and transcriptional activity. Treatment of MDA-MB-231 cells with pyrrolidine dithiocarbamate, an inhibitor of p65, or small interfering RNA knockdown of p65, blocked RON gene expression and MSP-mediated invasion of MDA-MB-231 cells. This is the first report showing the regulation of human RON gene expression by nuclear factor-kappaB and suggests a potential therapeutic role for curcumin in blocking RON tyrosine kinase-mediated invasion of carcinoma cells.

Topics: Binding Sites; Breast Neoplasms; Carcinoma; Curcumin; Down-Regulation; Drug Evaluation, Preclinical; Gene Expression Regulation, Neoplastic; Humans; Mutation; Neoplasm Invasiveness; NF-kappa B; Promoter Regions, Genetic; Protein Binding; Protein-Tyrosine Kinases; Receptor Protein-Tyrosine Kinases; RNA, Messenger; RNA, Small Interfering; Transfection; Tumor Cells, Cultured

TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) is a highly toxic environmental contaminant. When exposed to TCDD, mammalian cells undergo malignant transformation via abnormal intracellular signaling cascades, and the robust inductions of cytochrome P450 (CYP) enzymes are considered to mediate carcinogenesis by producing genotoxic metabolites. We here examined whether curcumin has preventive activity against TCDD-induced CYP production and cell transformation. Initially, the cellular levels of cytochrome P450 (CYP) 1A1 and 1B1 were examined, because these are known to generate estrogen metabolites that mediate genotoxic stress. Curcumin inhibited CYP1A1 and 1B1 induction by TCDD at the mRNA and protein levels. Notably, the nuclear levels of arylhydrocarbon receptor (AhR) and AhR nuclear translocator (ARNT) were decreased by curcumin, but those in the cytoplasm were not. It was also found that oxidative stress mediated the curcumin-induced degradations of AhR and ARNT. Furthermore, in vitro transformation assays showed that in normal human embryonic kidney cells and normal prostate cells curcumin prevents the anchorage-independent growth induced by TCDD. In conclusion, curcumin attenuates AhR/ARNT-mediated CYP induction by dioxin and presumably this mode-of-action may be responsible for the curcumin prevention of malignant transformation. The findings of this study should be found helpful in the design stage of pharmacodynamic studies for developing curcumin as a chemopreventive or anticancer agent.

Topics: Antigens, Polyomavirus Transforming; Aryl Hydrocarbon Receptor Nuclear Translocator; Breast Neoplasms; Carcinoma, Hepatocellular; Cell Line; Cell Line, Transformed; Cell Line, Tumor; Cell Transformation, Viral; Curcumin; Cytochrome P-450 Enzyme System; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Kidney; Liver Neoplasms; Male; Polychlorinated Dibenzodioxins; Prostatic Neoplasms; Reactive Oxygen Species; RNA, Small Interfering

To investigate the effect of curcumin on indoleamine 2, 3 -dioxygenase (IDO) expression induced by IFN-gamma in cancer cells.. A431, HeLa, HepG2, CNE2 cells were treated with curcumin for 24 hours, then the cell proliferation was detected by methyl thiazolyl tetrazolium (MTF) assay. The effects of curcumin on IDO expression induced by IFN-gamma in these cancer cells were demonstrated by Western blot. The transcription of interferon responsive factor-1 (IRF-1), which was a key transcription factor regulating IDO expression, was analyzed by reverse transcription polymerase chain reaction (RT-PCR) under the treatment of curcumin.. Curcumin inhibited the expression of IDO in these cancer cells. However, curcumin did not inhibit the transcription of IRF-1 in cancer cells.. Curcumin could inhibit the expression of IDO in cancer cells.

Topics: Breast Neoplasms; Cell Proliferation; Curcuma; Curcumin; Enzyme Inhibitors; Gene Expression Regulation, Enzymologic; HeLa Cells; Humans; Immunoblotting; Indoleamine-Pyrrole 2,3,-Dioxygenase; Interferon Regulatory Factor-1; Interferon-gamma; Liver Neoplasms; Reverse Transcriptase Polymerase Chain Reaction

Curcumin, a polyphenol natural product isolated from the rhizome of the plant Curcuma longa, has emerged as a promising anticancer therapeutic agent. However, the mechanism by which curcumin inhibits cancer cell functions such as cell growth, survival, and cell motility is largely unknown. We explored whether curcumin affects the function of integrin alpha(6)beta(4), a laminin adhesion receptor with an established role in invasion and migration of cancer cells. Here we show that curcumin significantly reduced alpha(6)beta(4)-dependent breast cancer cell motility and invasion in a concentration-dependent manner without affecting apoptosis in MDA-MB-435/beta4 (beta(4)-integrin transfectants) and MDA-MB-231 breast cancer cell lines. Further, curcumin selectively reduced the basal phosphorylation of beta(4) integrin (Y1494), which has been reported to be essential in mediating alpha(6)beta(4)-dependent phosphatidylinositol 3-kinase activation and cell motility. Consistent with this finding, curcumin also blocked alpha(6)beta(4)-dependent Akt activation and expression of the cell motility-promoting factor ENPP2 in MDA-MB-435/beta4 cell line. A multimodality approach using curcumin in combination with other pharmacologic inhibitors of alpha(6)beta(4) signaling pathways showed an additive effect to block breast cancer cell motility and invasion. Taken together, these findings show that curcumin inhibits breast cancer cell motility and invasion by directly inhibiting the function of alpha(6)beta(4) integrin, and suggest that curcumin can serve as an effective therapeutic agent in tumors that overexpress alpha(6)beta(4).

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Breast Neoplasms; Carcinoma; Cell Adhesion; Cell Movement; Curcumin; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Enzyme Inhibitors; Humans; Indoles; Integrin alpha6beta4; Neoplasm Invasiveness; Oncogene Protein v-akt; Phosphorylation; Piperazines; Signal Transduction; Sulfonamides; Tumor Cells, Cultured

The dietary antioxidant Curcumin has been proposed for cancer chemoprevention since it induces apoptosis and inhibits the formation of breast cancer metastases. Curcumin acts through the inhibition of phosphorylation of the inhibitor of kappa B (IkappaB), which in turn reduces the nuclear translocation of nuclear factor kappa B (NFkappaB), an inflammation- and cell survival-related transcription factor. However, it is not clear whether the strong antimetastatic effect can exclusively be explained by inhibition of NFkappaB. Here, we addressed the effects of Curcumin (IC(50) = 17 muM) in MDA-MB-231 breast cancer cells using microarray gene expression analyses. Among the 62 genes whose expression was significantly altered, we found the two inflammatory cytokines CXCL1 and -2 (Groalpha and -beta) that were downregulated. Further validation of the microarray results by quantitative real-time reverse transcription-polymerase chain reaction, western blots and enzyme-linked immunosorbent assay revealed that Curcumin impairs transcription of CXCL1 and -2 >24 h and reduces the corresponding proteins. Using small interfering RNA techniques, we elucidated the underlying molecular mechanism revealing that reduction of CXCL1 and -2 messenger RNA levels is NFkappaB dependent and requires intact IkappaBalpha expression. Moreover, CXCL1 and -2 silencing leads to downregulation of several metastasis-promoting genes among which we found the cytokine receptor CXCR4. We therefore suggest that the decrease of CXCL1 and -2 mediated by Curcumin is involved in the inhibition of metastasis.

Topics: Animals; Antioxidants; Breast Neoplasms; Cell Line, Tumor; Chemokine CXCL1; Chemokine CXCL2; Curcumin; DNA, Neoplasm; Down-Regulation; Female; Humans; Mice; Mice, Nude; NF-kappa B; Oligonucleotide Array Sequence Analysis; Reverse Transcriptase Polymerase Chain Reaction; RNA, Neoplasm; Transplantation, Heterologous

Both epigallocatechin gallate (EGCG) and curcumin have shown efficacy in various in vivo and in vitro models of cancer. This study was designed to determine the efficacy of these naturally derived polyphenolic compounds in vitro and in vivo, when given in combination. Studies in MDA-MB-231 cells demonstrated that EGCG + curcumin was synergistically cytotoxic and that this correlated with G(2)/M-phase cell cycle arrest. After 12 hr, EGCG (25 microM) + curcumin (3 microM) increased the proportion of cells in G(2)/M-phase to 263 +/- 16% of control and this correlated with a 50 +/- 4% decrease in cell number compared to control. To determine if this in vitro result would translate in vivo, athymic nude female mice were implanted with MDA-MB-231 cells and treated with curcumin (200 mg/kg/day, po), EGCG (25 mg/kg/day, ip), EGCG + curcumin, or vehicle control (5 ml/kg/day, po) for 10 weeks. Tumor volume in the EGCG + curcumin treated mice decreased 49% compared to vehicle control mice (p < 0.05), which correlated with a 78 +/- 6% decrease in levels of VEGFR-1 protein expression in the tumors. Curcumin treatment significantly decreased tumor protein levels of EGFR and Akt, however the expression of these proteins was not further decreased following combination treatment. Therefore, these results demonstrate that the combination of EGCG and curcumin is efficacious in both in vitro and in vivo models of ER alpha-breast cancer and that regulation of VEGFR-1 may play a key role in this effect.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Blotting, Western; Breast Neoplasms; Catechin; Cell Division; Cell Line, Tumor; Curcumin; ErbB Receptors; Estrogen Receptor alpha; Female; Flow Cytometry; Humans; Mice; Mice, Nude; Oncogene Protein v-akt; Organ Size; Vascular Endothelial Growth Factor Receptor-1; Weight Gain

Dissemination of metastatic cells probably occurs long before diagnosis of the primary tumor. Metastasis during early phases of carcinogenesis in high risk patients is therefore a potential prevention target. The plant polyphenol Curcumin has been proposed for dietary prevention of cancer. We therefore examined its effects on the human breast cancer cell line MDA-MB-231 in vitroand in a mouse metastasis model. Curcumin strongly induces apoptosis in MDA-MB-231 cells in correlation with reduced activation of the survival pathway NFkappaB, as a consequence of diminished IotakappaB and p65 phosphorylation. Curcumin also reduces the expression of major matrix metalloproteinases (MMPs) due to reduced NFkappa B activity and transcriptional downregulation of AP-1. NFkappa B/p65 silencing is sufficient to downregulate c-jun and MMP expression. Reduced NFkappa B/AP-1 activity and MMP expression lead to diminished invasion through a reconstituted basement membrane and to a significantly lower number of lung metastases in immunodeficient mice after intercardiac injection of 231 cells (p=0.0035). 68% of Curcumin treated but only 17% of untreated animals showed no or very few lung metastases, most likely as a consequence of down-regulation of NFkappa B/AP-1 dependent MMP expression and direct apoptotic effects on circulating tumor cells but not on established metastases. Dietary chemoprevention of metastases appears therefore feasible.

Topics: Animals; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Survival; Curcumin; Female; Flavonoids; Forkhead Transcription Factors; Humans; I-kappa B Proteins; Lung Neoplasms; Matrix Metalloproteinases; Mice; Mice, SCID; Neoplasm Invasiveness; Neoplasm Metastasis; NF-kappa B; Phenols; Phosphorylation; Polyphenols; Transcription Factor AP-1; Transfection; Xenograft Model Antitumor Assays

Curcumin has anticarcinogenic and chemopreventive properties in a variety of experimental cancer models. Our in vitro studies have shown that curcumin inhibits cell growth and induces apoptosis in MCF-7, a human breast carcinoma cell line. The insulin-like growth factor-1 (IGF-1) system, including IGFs (IGF-1 and IGF-2), IGF-1R (IGF-1 receptor) and IGFBPs (IGF binding proteins), has been implicated to play a critical role in the development of breast cancer. The aim of the present study was to investigate whether the growth inhibitory effects of curcumin were related to changes of the IGF-1 system in MCF-7 cells. IGF-1 at 50 microg/l in serum-free medium produced maximum proliferation and minimized apoptosis. However, curcumin exhibited a potent ability to blunt IGF-1-stimulated MCF-7 cell growth and reverse the IGF-1-induced apoptosis resistance. To determine whether curcumin intervenes in IGF-1 or IGFBP-3 secretion, MCF-7 cells were incubated in serum-free medium in the presence of various concentrations of curcumin for indicated time periods. Curcumin decreased the secretion of IGF-1 with a concomitant increase of IGFBP-3 in a dose-dependent manner. Receptor tyrosine kinase assays revealed that IGF-1-stimulated IGF-1R tyrosine kinase activation was also abrogated by curcumin in a dose-dependent manner. Real-time fluorescence quantitative reverse transcriptase-polymerase chain reaction (RFQ-RT-PCR) further revealed that curcumin suppressed IGF-1R gene expression at transcriptional level. In conclusion, the inhibition of cell growth and induction of apoptosis by curcumin in MCF-7 cells might be mediated, at least partially, by its ability to down-regulate the IGF-1 axis.

Topics: Annexin A5; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Curcumin; Dose-Response Relationship, Drug; Drug Synergism; Humans; Insulin-Like Growth Factor I; Polymerase Chain Reaction; Receptor, IGF Type 1; Time Factors

An important characteristic of tumors is that they at some point in their development overcome the surveillance of the immune system. Tumors secrete exosomes, multivesicular bodies containing a distinct set of proteins that can fuse with cells of the circulating immune system. Purified exosomes from TS/A breast cancer cells, but not non-exosomal fractions, inhibit (at concentrations of nanograms per ml protein) IL-2-induced natural killer (NK) cell cytotoxicity. The dietary polyphenol, curcumin (diferuloylmethane), partially reverses tumor exosome-mediated inhibition of natural killer cell activation, which is mediated through the impairment of the ubiquitin-proteasome system. Exposure of mouse breast tumor cells to curcumin causes a dose-dependent increase in ubiquitinated exosomal proteins compared to those in untreated TS/A breast tumor cells. Furthermore, exosomes isolated from tumor cells pretreated with curcumin have a much attenuated inhibition of IL-2 stimulated NK cell activation. Jak3-mediated activation of Stat5 is required for tumor cytotoxicity of IL-2 stimulated NK cells. TS/A tumor exosomes strongly inhibit activation of Stat5, whereas the tumor exosomes isolated from curcumin-pretreated tumor cells have a lowered potency for inhibition of IL-2 stimulated NK cell cytotoxicity. These data suggest that partial reversal of tumor exosome-mediated inhibition of NK cell tumor cytotoxicity may account for the anti-cancer properties of curcumin.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Curcumin; Enzyme Activation; Female; Humans; Immune System; Interleukin-2; Janus Kinase 3; Killer Cells, Natural; Mice; Neoplasm Proteins; Ubiquitin

Arachidonate metabolites are important regulators of human breast cancer cells. Production of bioactive lipids are frequently initiated by the enzyme phospholipase A2 which releases arachidonic acid (AA) that is rapidly metabolized by cyclooxygenases (COX) or lipoxygenases (LO) to other highly potent lipids.. In this study we screened a number of inhibitors which blocked specific pathways of AA metabolism for their antiproliferative activity on MCF-7 wild type and MCF-7 ADR drug resistant breast cancer cells. The toxicity of these inhibitors was further tested on human bone marrow cell proliferation.. Inhibitors of LO pathways (specifically the 5-LO pathway) were most effective in blocking proliferation. Inhibitors of platelet activating factor, a byproduct of arachidonate release, were also effective antiproliferative agents. Curcumin, an inhibitor of both COX and LO pathways of eicosanoid metabolism, was 12-fold more effective in blocking proliferation of the MCF-7 ADRs cells compared to MCF-7 wild type (WT) cells. These inhibitors that effectively blocked the proliferation of breast cancer cells showed varying degrees of toxicity to cultures of human bone marrow cells. We observed greater toxicity to bone marrow cells with inhibitors that interfere with the utilization of AA in contrast to those which block utilization of its downstream metabolites. MK-591, MK-886, PCA-4248, and AA-861 blocked proliferation of breast cancer cells but showed no toxicity to bone marrow cells.. These inhibitors were effective in blocking the proliferation of breast cancer cells and may be potentially useful in human breast cancer therapy.

Topics: Arachidonic Acid; Breast Neoplasms; Curcumin; Cyclooxygenase Inhibitors; Doxorubicin; Drug Resistance, Neoplasm; Humans; Lipoxygenase Inhibitors; Signal Transduction; Tumor Cells, Cultured

We examined the effects of curcumin and of its isoxazole analogue MR 39 in the MCF-7 breast cancer cell line and in its multidrug-resistant (MDR) variant MCF-7R. In comparison with MCF-7, MCF-7R lacks estrogen receptor alpha (ERalpha) and overexpressess P-glycoprotein (P-gp), different IAPs (inhibitory of apoptosis proteins) and COX-2. Through analyses of the effects on cell proliferation, cycling and death, we have observed that the antitumor activity of curcumin and of the more potent (approximately two-fold) MR 39 is at least equal in the MDR cell line compared to the parental MCF-7. Similar results were observed also in an MDR variant of HL-60 leukemia. RT-PCR evaluations performed in MCF-7 and MCF-7R showed that curcumin or MR 39 produced early modifications in the amounts of relevant gene transcripts, which, however, were mostly diverse (i.e. represented by decreases in IAPs and COX-2 in MCF-7R versus reductions in Bcl-2 and Bcl-XL as well as increases in the Bcl-XS/Bcl-XL ratio in MCF-7) in the two cell lines. These results could not be explained by an involvement of NF-kappaB (p65 subunit) or STAT3, since the low nuclear levels of these transcription factors present in MCF-7 were only slightly, though significantly, elevated in MCF-7R; moreover, curcumin or MR 39 caused minor changes in NF-kappaB or STAT3 activation. Overall, these data underline that curcumin or MR 39 antitumor activities are not hampered by P-gp expression or lack of ERalpha in breast cancer cells. Remarkably, the agents appeared to modify their molecular effects according to the diverse gene expression patterns existing in the MDR and in the parental MCF-7. Clearly, the structure and properties of curcumin can form the basis for the development of antitumor compounds that are more effective against both chemosensitive and MDR cells.

Topics: Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cell Cycle; Cell Death; Cell Line, Tumor; Cell Proliferation; Curcumin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Gene Expression; Humans; STAT3 Transcription Factor; Transcription Factor RelA

In this study, we show that the novel synthetic curcumin analog, EF24, induces cell cycle arrest and apoptosis by means of a redox-dependent mechanism in MDA-MB-231 human breast cancer cells and DU-145 human prostate cancer cells. Cell cycle analysis demonstrated that EF24 causes a G2/M arrest in both cell lines, and that this cell cycle arrest is followed by the induction of apoptosis as evidenced by caspase-3 activation, phosphatidylserine externalization and an increased number of cells with a sub-G1 DNA fraction. In addition, we demonstrate that EF24 induces a depolarization of the mitochondrial membrane potential, suggesting that the compound may also induce apoptosis by altering mitochondrial function. EF24, like curcumin, serves as a Michael acceptor reacting with glutathione (GSH) and thioredoxin 1. Reaction of EF24 with these agents in vivo significantly reduced intracellular GSH as well as oxidized GSH in both the wild-type and Bcl-xL overexpressing HT29 human colon cancer cells. We therefore propose that the anticancer effect of a novel curcumin analog, EF24, is mediated in part by redox-mediated induction of apoptosis.

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Caspase 3; Caspases; Cell Cycle; Colonic Neoplasms; Curcumin; Female; Humans; Male; Oxidation-Reduction; Prostatic Neoplasms; Reactive Oxygen Species; Tumor Cells, Cultured

Curcumin (diferuloylmethane) is known to induce apoptosis in tumor cells. In asynchronous cultures, with time-lapse video-micrography in combination with quantitative fluorescence microscopy, we have demonstrated that curcumin induces apoptosis at G(2) phase of cell cycle in deregulated cyclin D1-expressed mammary epithelial carcinoma cells, leaving its normal counterpart unaffected. In our search toward delineating the molecular mechanisms behind such differential activities of curcumin, we found that it selectively increases p53 expression at G(2) phase of carcinoma cells and releases cytochrome c from mitochondria, which is an essential requirement for apoptosis. Further experiments using p53-null as well as dominant-negative and wild-type p53-transfected cells have established that curcumin induces apoptosis in carcinoma cells via a p53-dependent pathway. On the other hand, curcumin reversibly inhibits normal mammary epithelial cell cycle progression by down-regulating cyclin D1 expression and blocking its association with Cdk4/Cdk6 as well as by inhibiting phosphorylation and inactivation of retinoblastoma protein. In addition, curcumin significantly up-regulates cell cycle inhibitory protein (p21Waf-1) in normal cells and arrests them in G(0) phase of cell cycle. Therefore, these cells escape from curcumin-induced apoptosis at G(2) phase. Interestingly, these processes remain unaffected by curcumin in carcinoma cells where cyclin D1 expression is high. Similarly, in ectopically overexpressed system, curcumin cannot down-regulate cyclin D1 and thus block cell cycle progression. Hence, these cells progress into G(2) phase and undergo apoptosis. These observations together suggest that curcumin may have a possible therapeutic potential in breast cancer patients.

Topics: Animals; Antineoplastic Agents; Apoptosis; Breast; Breast Neoplasms; Cell Cycle Proteins; Cell Line; Cell Line, Tumor; Curcumin; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p21; Epithelial Cells; Female; G2 Phase; Humans; Mice; Mice, Knockout; Microscopy, Fluorescence; Microscopy, Video; NIH 3T3 Cells; Tumor Suppressor Protein p53

Currently, there is no effective therapy for metastatic breast cancer after surgery, radiation, and chemotherapy have been used against the primary tumor. Because curcumin suppresses nuclear factor-kappaB (NF-kappaB) activation and most chemotherapeutic agents activate NF-kappaB that mediates cell survival, proliferation, invasion, and metastasis, we hypothesized that curcumin would potentiate the effect of chemotherapy in advanced breast cancer and inhibit lung metastasis. We tested this hypothesis using paclitaxel (Taxol)-resistant breast cancer cells and a human breast cancer xenograft model. As examined by electrophoretic mobility gel shift assay, paclitaxel activated NF-kappaB in breast cancer cells and curcumin inhibited it; this inhibition was mediated through inhibition of IkappaBalpha kinase activation and IkappaBalpha phosphorylation and degradation. Curcumin also suppressed the paclitaxel-induced expression of antiapoptotic (XIAP, IAP-1, IAP-2, Bcl-2, and Bcl-xL), proliferative (cyclooxygenase 2, c-Myc, and cyclin D1), and metastatic proteins (vascular endothelial growth factor, matrix metalloproteinase-9, and intercellular adhesion molecule-1). It also enhanced apoptosis. In a human breast cancer xenograft model, dietary administration of curcumin significantly decreased the incidence of breast cancer metastasis to the lung and suppressed the expression of NF-kappaB, cyclooxygenase 2, and matrix metalloproteinase-9. Overall, our results indicate that curcumin, which is a pharmacologically safe compound, has a therapeutic potential in preventing breast cancer metastasis possibly through suppression of NF-kappaB and NF-kappaB-regulated gene products.

Topics: Animals; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Survival; Curcumin; Cyclooxygenase 2; Drug Synergism; Female; Gene Expression; Humans; Immunohistochemistry; Ki-67 Antigen; Lung Neoplasms; Mammary Neoplasms, Experimental; Matrix Metalloproteinase 9; Mice; Mice, Nude; NF-kappa B; Paclitaxel; Promoter Regions, Genetic; Signal Transduction; Xenograft Model Antitumor Assays

Vascular endothelial growth factor (VEGF) and interleukin-8/CXCL8 (IL-8) are prominent pro-angiogenic and pro-metastatic proteins that represent negative prognostic factors in many types of cancer. Hypoxia is thought to be the primary environmental cause of VEGF and IL-8 expression in solid tumors. We hypothesized that a lack of nutrients other than oxygen could stimulate the expression of these factors and previously demonstrated that expression of VEGF and IL-8 is responsive to amino acid deprivation. In the present study, we examined the effect of glutamine availability on the expression of these factors as well as the role of transcription factors NFkappaB and activating protein-1 (AP-1) in the response of TSE human breast carcinoma cells to glutamine deprivation. VEGF and IL-8 secretion and mRNA levels were dramatically induced by glutamine deprivation. mRNA stabilization contributed to this response. Glutamine deprivation increased NFkappaB (p65/p50) and AP-1 (Fra-1/c-Jun+JunD) DNA-binding activities. Blocking NFkappaB and AP-1 activation with curcumin as well as expression of dominant inhibitors, inhibitor of nuclear factor-kappaB (IkappaB) super repressor (IkappaBM), and a mutant form of c-Fos (A-Fos) demonstrated that the activation of NFkappaB and AP-1 transcription factors was necessary for the induction of IL-8 expression but dispensable for the induction of VEGF expression. A macro-array containing 111 NFkappaB target genes identified a total of 17 that were up-regulated 2-fold or more in response to glutamine deprivation. These included growth regulated oncogene alpha (GROalpha/GRO1/CXCL1), another neutrophil chemoattractant implicated in tumor angiogenesis and metastasis.

Topics: Breast Neoplasms; Cell Line, Tumor; Chemokine CXCL1; Chemokines, CXC; Curcumin; DNA, Neoplasm; Gene Expression Regulation, Neoplastic; Glutamine; Humans; Intercellular Signaling Peptides and Proteins; Interleukin-8; NF-kappa B; Oligonucleotide Array Sequence Analysis; RNA, Messenger; Transcription Factor AP-1; Transcription, Genetic; Up-Regulation; Vascular Endothelial Growth Factor A

To study the reversal mechanism of adriamycin (ADM) resistance in human breast cancer cell line MCF-7/ADM by beta-elemene (beta-ELE), a wide spectrum anticancer drug derived from the Chinese herb Curcuma chaeocaulis.. Sensitivity to ADM of MCF-7/ADM cells was studied by MTT assay. Intracellular accumulation of ADM in MCF-7/ADM cells was observed by fluorescent-spectrophotometry. Expression of bcl-2 protein was detected by flow cytometry.. A non-cytotoxic dose (6 micro g/ml) and a weakly cytotoxic dose (13 micro g/ml) of beta-ELE could significantly enhance the cytotoxic effects of ADM on MCF-7/ADM cells to 1.4 and 2.2 fold as compared to the beta-ELE untreated control cells. The intracellular concentration of ADM in MCF-7/ADM cells was significantly increased after treatment with beta-ELE (P < 0.01). The expression of bcl-2 protein in MCF-7/ADM cells was reduced from 90.2% to 70.0% (P < 0.05).. beta-ELE could partially reverse the drug resistance to ADM in MCF-7/ADM, which is related to the increased accumulation of intracellular ADM and the decreased expression of bcl-2.

Topics: Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cell Line, Tumor; Curcuma; Doxorubicin; Drug Resistance, Neoplasm; Female; Humans; Plants, Medicinal; Sesquiterpenes

It had been observed that BRM-SJS had antitumor effect in our clinical practice. This study was designed to investigate the antitumor activity of BRM-SJS, and mechanism of its action.. In vitro antitumor experiments with MTT method, meanwhile cell morphology, flow cytometry, and agarose gel electrophoresis were performed for determining apoptosis in several tumor cell lines.. BRM-SJS had antitumor effects on human Suzhou human glioma (SHG-44), breast carcinoma (MCF-7), and human pancreas carcinoma (PANC1) in vitro, the IC50 values of BRM-SJS were 0. 299 mg/ml, 1.853 mg/ml and 9.416 mg/ml respectively. At the 2. 5 mg of BRM-SJS on SHG-44 and MCF-7, marked morphological changes, including cell shrinkage and condensation of chromosomes, were observed with electric microscope. The increase of apoptosis in SHG-44 and MCF-7 cells treated with BRM-SJS extracts 0.625 -2.5 mg for 14 -48 h was observed by Annexin-V/PI flow cytometry analysis. Agarose gel electrophoresis of DNA from SHG-44 and MCF-7 cells treated with BRM-SJS extracts 1.25 -5 mg for 24 h or 48 h showed marked DNA Ladder pattern.. Antitumor activity of BRM-SJS may be related with inducement of apoptosis of tumor cells.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Breast Neoplasms; Capsules; Cell Line, Tumor; Cell Proliferation; Curcuma; Drug Combinations; Drugs, Chinese Herbal; Female; Glioma; Humans; Pancreatic Neoplasms; Plants, Medicinal; Scutellaria

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Curcumin; Diet; Female; HT29 Cells; Humans; NF-kappa B

Several papers have reported that low level of genistein (<8 microM), the major bioactive component of isoflavones, stimulates the growth of MCF-7 cells. In the present study, we found that genistein-induced growth stimulation of MCF-7 cells is inhibited in the presence of Cu(2+) (5 microM). Genistein induces the release of nitric oxide in MCF-7 cells in a concentration-dependent manner. The release of nitric oxide was inhibited by N(G)-nitro-L-arginine methyl ester, suggesting the possibility of the activation of nitric oxide synthase. The growth of MCF-7 cells also increases in the presence of low levels of sodium nitriprusside (<10 microM), a nitric oxide donor compound, while high levels (>25 microM) are toxic. The sodium nitroprusside-induced growth of MCF-7 cells is drastically suppressed in the presence of Cu(2+) (5 microM). This parallel behavior between Cu(2+)-genistein and Cu(2+)-sodium nitroprusside mixtures suggests that Cu(2+) and/or copper-protein complexes, that may be formed in the media, may be reacting with nitric oxide or nitric oxide-derived reactive species. The products of these reactions may be responsible for the toxic effects of these mixtures. In contrast, the effect of curcumin that inhibits the growth of both estrogen receptor-positive and -negative breast tumor cells appreciably decreased in the presence of Cu(2+). Since copper is known to overwhelmingly bind with proteins, present data suggest that an increase in copper-protein moieties or complexes formed in the serum containing media and their reactions with nitric oxide may be responsible for their toxic effects. Further studies are needed to characterize these reactions.

Topics: Breast Neoplasms; Cell Division; Cell Line, Tumor; Copper; Curcumin; Genistein; Humans; Nitric Oxide; Nitric Oxide Donors; Nitroprusside; Receptors, Estrogen

To study the suppressive effects of curcumin on breast carcinoma cells and the mechanism.. Estrogen receptor (ER) positive human breast cancer line MCF-7 and ER negative human breast cancer line MDA-MB-231 were cultured 17-beta estradiol and curcumin were added into the culture. Northern blot hybridization and Western blots were performed to detect the expression of mRNA and protein. The human ERE promoter activity was analyzed by transient transfection with CAT-reporter constructs. Invasion experiments were conducted with a Matrigel invasion chamber.. Curcumin inhibit the proliferation in both estrogen receptor (ER) positive MCF-7 cells and ER negative MDA-MB-231 cells. Curcumin's antiproliferative effects are estrogen dependent in ER positive MCF-7 cells. Curcumin inhibits the expression of ER downstream genes including pS2 and TGF-alpha (transforming growth factor-alpha) in ER-positive MCF-7 cells, and this inhibition is also dependent on the presence of estrogen. In addition, curcumin exerts strong anti-invasive effects in vitro which was not estrogen dependent in the ER-negative MDA-MB-231 breast cancer cells. These anti-invasive effects appeared to be mediated through the down-regulation of MMP-2 (matrix metalloproteinase) and the up-regulation of TIMP-1 (tissue inhibitor of metalloproteinase). Curcumin inhibited the transcript levels of two major angiogenesis factors VEGF (vascular endothelial growth factor) and b-FGF (basic fibroblast growth factor) in ER-negative MDA-MB-231 cells.. Curcumin exerts multiple suppressive effects on breast carcinoma cells;it's mechanism of chemoprevention is pleiotropic.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Division; Cell Line, Tumor; Curcumin; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; Female; Humans; Proteins; Receptors, Estrogen; Transforming Growth Factor alpha; Trefoil Factor-1; Tumor Suppressor Proteins

The aim of this study was to determine the mechanisms of curcumin-induced human breast cancer cell apoptosis. From quantitative image analysis data showing an increase in the percentage of cells with a sub-G0/G1 DNA content, we demonstrated curcumin-induced apoptosis in the breast cancer cell line MCF-7, in which expression of wild-type p53 could be induced. Apoptosis was accompanied by an increase in p53 level as well as its DNA-binding activity followed by Bax expression at the protein level. Further experiments using p53-null MDAH041 cell as well as low and high p53-expressing TR9-7 cell, in which p53 expression is under tight control of tetracycline, established that curcumin induced apoptosis in tumor cells via a p53-dependent pathway in which Bax is the downstream effector of p53. This property of curcumin suggests that this molecule could have a possible therapeutic potential in breast cancer patients.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; bcl-2-Associated X Protein; Breast Neoplasms; Cell Cycle; Curcumin; Female; Gene Expression; Humans; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Tumor Cells, Cultured; Tumor Suppressor Protein p53

In our study, we present experimental evidence suggesting that curcumin exerts multiple different suppressive effects on human breast carcinoma cells in vitro. Our experiments demonstrate that curcumin's antiproliferative effects are estrogen dependent in ER (estrogen receptor)-positive MCF-7 cells, being more pronounced in estrogen-containing media and in the presence of exogenous 17-beta estradiol. Curcumin inhibits the expression of ER downstream genes including pS2 and TGF-beta (transforming growth factor) in ER-positive MCF-7 cells, and this inhibition is also dependent on the presence of estrogen. Curcumin also decreases ERE (estrogen responsive element)-CAT activities induced by 17-beta estradiol. In addition, we demonstrate that curcumin exerts strong anti-invasive effects in vitro that are not estrogen dependent in the ER-negative MDA-MB-231 breast cancer cells. These anti-invasive effects appear to be mediated through the downregulation of MMP-2 (matrix metalloproteinase) and the upregulation of TIMP-1 (tissue inhibitor of metalloproteinase), 2 common effector molecules that have been implicated in regulating tumor cell invasion. Our study also demonstrates that curcumin inhibits the transcript levels of 2 major angiogenesis factors VEGF (vascular endothelial growth factor) and b-FGF (basic fibroblast growth factor) mainly in ER-negative MDA-MB-231 cells.

Topics: Antineoplastic Agents; Breast Neoplasms; Carcinoma; Cell Division; Curcumin; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; Dose-Response Relationship, Drug; Estrogen Antagonists; Female; Humans; Neoplasm Invasiveness; Neovascularization, Pathologic; Proteins; Receptors, Estrogen; Response Elements; RNA, Neoplasm; Transcription, Genetic; Transforming Growth Factor alpha; Trefoil Factor-1; Tumor Cells, Cultured; Tumor Suppressor Proteins

The dietary phytochemical curcumin possesses anti-inflammatory, -oxidant, and cytostatic properties, and exhibits significant potential as a chemopreventative agent in humans. Although many cell types are arrested in the G2/M-phase of the cell cycle after curcumin treatment, the mechanisms by which this occurs are not well understood. The purpose of this study was to examine the effects of curcumin on the cell cycle of MCF-7 breast cancer cells to determine whether growth arrest is associated with structural changes in cellular organization during mitosis. For this purpose, MCF-7 breast cancer cells were treated with 10-20 microM curcumin, and the effects on cell proliferation and mitosis studied. Structural changes were monitored by immunolabeling cells with antibodies to a number of cytoplasmic and nuclear proteins, including beta-tubulin, NuMA, lamins A/C and B1, lamin B receptor, and centromere antigens. At the concentrations used, a single dose of curcumin does not induce significant apoptosis, but is highly effective in inhibiting cell proliferation for over 6 days. During the first 24-48 h of treatment, many cells are arrested in M-phase, and DNA synthesis is almost completely inhibited. Remarkably, arrested mitotic cells exhibit monopolar spindles, and chromosomes do not undergo normal anaphase movements. After 48 h, most cells eventually leave M-phase, and many form multiple micronuclei instead of individual daughter nuclei. These observations indicate that the curcumin-induced G2/M arrest previously described for MCF-7 cells is due to the assembly of aberrant, monopolar mitotic spindles that are impaired in their ability to segregate chromosomes. The production of cells with extensive micronucleation after curcumin treatment suggests that at least some of the cytostatic effects of this phytochemical are due to its ability to disrupt normal mitosis, and raises the possibility that curcumin may promote genetic instability under some circumstances.

Topics: Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cell Cycle; Cell Division; Curcumin; Female; Humans; Micronuclei, Chromosome-Defective; Mitosis; Spindle Apparatus; Tumor Cells, Cultured

Curcumin, the major component of the spice turmeric, is used as a coloring and flavoring additive in many foods and has attracted interest because of its anti-inflammatory and chemopreventive activities. However, this agent also inhibits the generation of reactive oxygen species (ROS) and the c-Jun NH(2)-terminal kinase (JNK) pathway, and because many chemotherapeutic drugs generate ROS and activate JNK in the course of inducing apoptosis, we considered the possibility that curcumin might antagonize their antitumor efficacy. Studies in tissue culture revealed that curcumin inhibited camptothecin-, mechlorethamine-, and doxorubicin-induced apoptosis of MCF-7, MDA-MB-231, and BT-474 human breast cancer cells by up to 70%. Inhibition of programmed cell death was time and concentration dependent, but occurred after relatively brief 3-h exposures, or at curcumin concentrations of 1 microM that have been documented in Phase I chemoprevention trials. Under these conditions, curcumin exhibited antioxidant properties and inhibited both JNK activation and mitochondrial release of cytochrome c in a concentration-dependent manner. Using an in vivo model of human breast cancer, dietary supplementation with curcumin was found to significantly inhibit cyclophosphamide-induced tumor regression. Such dietary supplementation was accompanied by a decrease in the activation of apoptosis by cyclophosphamide, as well as decreased JNK activation. These findings support the hypothesis that dietary curcumin can inhibit chemotherapy-induced apoptosis through inhibition of ROS generation and blockade of JNK function, and suggest that additional studies are needed to determine whether breast cancer patients undergoing chemotherapy should avoid curcumin supplementation, and possibly even limit their exposure to curcumin-containing foods.

Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Apoptosis; Breast Neoplasms; Camptothecin; Curcumin; Cyclophosphamide; Cytochrome c Group; Diet; Drug Interactions; Enzyme Activation; Humans; JNK Mitogen-Activated Protein Kinases; Mice; Mice, Nude; Mitochondria; Mitogen-Activated Protein Kinases; Reactive Oxygen Species; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

The inhibitory effect of curcumin, the yellow-colored pigment from turmeric, on telomerase activity was analyzed in human mammary epithelial (MCF-10A) and breast cancer (MCF-7) cells. Telomerase activity in MCF-7 cells is 6.9-fold higher than that of human mammary epithelial cells. In MCF-7 cells, telomerase activity decreased with increasing concentrations of curcumin, inhibiting about 93.4% activity at 100 microM concentration. The inhibition of telomerase activity in MCF-7 cells may be due to down-regulation of hTERT expression. Increasing concentrations of curcumin caused a steady decrease in the level of hTERT mRNA in MCF-7 cells whereas the level of hTER and c-myc mRNAs remained the same. Our results suggest that curcumin inhibits telomerase activity by down-regulating hTERT expression in breast cancer cells and this down-regulation is not through the c-myc pathway.

Topics: Breast Neoplasms; Curcumin; DNA-Binding Proteins; Dose-Response Relationship, Drug; Down-Regulation; Enzyme Inhibitors; Epithelial Cells; Female; Humans; Proto-Oncogene Proteins c-myc; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Neoplasm; Telomerase; Tumor Cells, Cultured

Curcumin, a well-known dietary pigment derived from Curcuma longa, has been shown to be a potent antiinflammatory, antioxidant, and anticarcinogenic compound. The present study was designed to investigate the cytotoxic potential of curcumin against a range of human tumor cell lines in an attempt to understand its mechanism of action, which may lead to its possible therapeutic applications. We have shown that different cancer cell lines differ in their sensitivity to curcumin. Cell lines established from malignancies like leukemia, breast, colon, hepatocellular, and ovarian carcinomas underwent apoptosis in the presence of curcumin, whereas cell lines from lung, kidney, prostate, cervix, CNS malignancies, and melanomas showed resistance to the cytotoxic effects of curcumin. Sensitivity of the cancer cell lines to curcumin correlated with the generation of superoxide radicals as determined by the reduction of ferricytochrome C. Curcumin-resistant tumor cell lines showed significantly higher production of Hsp70, thus mounting a stress response and protecting the cells from the apoptotic cell death. These observations yield clues toward understanding the regulation of the cell death machinery by the stress proteins. Interestingly, curcumin had no effect on nontransformed cell lines, which showed neither superoxide generation nor the induction of a stress response. These observations demonstrate that curcumin is an interesting molecule with varied actions, depending on the cell type.

Topics: Animals; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Line; Colonic Neoplasms; Curcumin; Cytoprotection; Drug Resistance, Neoplasm; fas Receptor; Female; Fibroblasts; HSP70 Heat-Shock Proteins; Humans; Leukemia; Liver Neoplasms; Neoplasms; Ovarian Neoplasms; Rats; Reactive Oxygen Species; Tumor Cells, Cultured

Curcumin has anti-inflammatory, antiproliferative, and antitumor effects. To understand the chemopreventive mechanism of curcumin against human malignancies, the cellular and molecular changes induced by this agent in human mammary epithelial (MCF-10A) and breast carcinoma (MCF- 7/TH) cell lines were investigated. The human multidrug- resistant breast cancer cell line was 3.5 fold more sensitive to curcumin than the mammary epithelial cell line. Even though both cell lines accumulated a similar amount of curcumin, a significantly higher percentage of apoptotic cells was induced in breast cancer cells compared to a very low percentage of apoptosis in mammary epithelial cells. Incubation of breast cancer cells with 20 and 40 microM curcumin for 24 h induced G2 block and sub-G0/G1 cell population, respectively. Curcumin treatment caused a reduction in the expression of Ki67, PCNA, and p53 mRNAs in breast cancer cells. The human mammary epithelial cell line showed a down-regulation of p21 mRNA and an up-regulation of Bax mRNA expression with curcumin treatment. The results suggest that apoptosis is involved in the curcumin-induced inhibition of tumor cell growth, and genes associated with cell proliferation and apoptosis may be playing a role in the chemopreventive action of curcumin.

Topics: Algorithms; Apoptosis; Breast; Breast Neoplasms; Cell Division; Cell Line; Clone Cells; Curcumin; Epithelial Cells; Female; Gene Expression; Humans; RNA, Messenger; Tumor Cells, Cultured

We examined the interaction of curcumin, a dietary constituent and chemopreventive compound, with the carcinogen activation pathway mediated by the aryl hydrocarbon receptor (AhR) in MCF-7 mammary epithelial carcinoma cells. Curcumin caused a rapid accumulation of cytochrome P450 1A1 (CYP1A1) mRNA in a time- and concentration-dependent manner, and CYP1A1 monooxygenase activity increased as measured by ethoxyresorufin-O-deethylation. Curcumin activated the DNA-binding capacity of the AhR for the xenobiotic responsive element of CYP1A1 as measured by the electrophoretic-mobility shift assay (EMSA). Curcumin was able to compete with the prototypical AhR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin for binding to the AhR in isolated MCF-7 cytosol, indicating that it interacts directly with the receptor. Although curcumin could activate the AhR on its own, it partially inhibited the activation of AhR, as measured by EMSA, and partially decreased the accumulation of CYP1A1 mRNA caused by the mammary carcinogen dimethylbenzanthracene (DMBA). Curcumin competitively inhibited CYP1A1 activity in DMBA-treated cells and in microsomes isolated from DMBA-treated cells. Curcumin also inhibited the metabolic activation of DMBA, as measured by the formation of DMBA-DNA adducts, and decreased DMBA-induced cytotoxicity. These results suggest that the chemopreventive effect of curcumin may be due, in part, to its ability to compete with aryl hydrocarbons for both the AhR and CYP1A1. Curcumin may thus be a natural ligand and substrate of the AhR pathway.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Anticarcinogenic Agents; Biotransformation; Breast Neoplasms; Carcinogens; Curcumin; Cytochrome P-450 CYP1A1; DNA-Binding Proteins; Humans; Polychlorinated Dibenzodioxins; Protein Binding; Receptors, Aryl Hydrocarbon; RNA, Messenger; Tumor Cells, Cultured

Curcumin, demethoxycurcumin and bisdemethoxycurcumin are the yellow coloring phenolic compounds isolated from the spice turmeric. This study was part of a program correlating the biological activity and molecular structure of antitumor agents; the effect of these curcuminoids and cyclocurcumin (Cyclocur) was examined on the proliferation of MCF-7 human breast tumor cells. Curcuminoids appeared to be potent inhibitors, whereas Cyclocur was less inhibitory. To contribute to our understanding of the mechanism of antiproliferative activity of curcumin, cell cycle analysis was performed by propidium iodide staining and a flow cytometry technique. Curcumin exerts a cytostatic effect at G2/M which explains its antiproliferative activity. The presence of the diketone moiety in the curcumin molecule seems to be essential for the inhibitory activity.

Topics: Anticarcinogenic Agents; Breast Neoplasms; Cell Cycle; Cell Division; Coumaric Acids; Curcumin; Diarylheptanoids; Humans; Structure-Activity Relationship; Tumor Cells, Cultured

Many environmental chemicals and pesticides have been found to be estrogenic and have been shown to stimulate the growth of estrogen receptor-positive (ER-positive) human breast cancer cells. Since it is difficult to avoid human exposure to environmental estrogens, a potentially important area of research is the development of dietary strategies to prevent the stimulated growth of breast tumors by environmental estrogens. In this context, the inhibitory action of curcumin and a combination of curcumin and isoflavonoids were studied in ER-positive human breast cancer cells (MCF-7 and T47D) and ER-negative MDA-MB-231 cells induced by the pesticide o,p'-DDT and the environmental pollutants 4-nonylphenol and 4-octylphenol. The median inhibitory concentration (IC50) for curcumin in T47D cells was 10 microM when measured at either a 48-hr or a 6-day incubation time. The IC50 value for curcumin was within the 8-10 microM range for inhibiting the growth of T47D cells induced by a 10- microM concentration each of 4-nonylphenol, 4-octylphenol, and o, p'-DDT. The IC50 for curcumin in MCF-7 cells induced by 10 microM of either o,p'-DDT, 4-octylphenol, or 4-nonylphenol were 9, 39, and >50 microM, respectively. A combination of curcumin and isoflavonoids was able to inhibit the induced growth of ER-positive cells up to 95%. For MDA-MB-231 cells, the IC50 for curcumin was 17 microM, which was reduced to 11 microM in the presence of 25 microM genistein. Curcumin and genistein induce drastic changes in the morphological shape of both ER-positive and ER-negative cells. Data presented here indicate that a mixture of curcumin and isoflavonoids is the most potent inhibitor against the growth of human breast tumor cells. These data suggest that combinations of natural plant compounds may have preventive and therapeutic applications against the growth of breast tumors induced by environmental estrogens.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Division; Cell Transformation, Neoplastic; Curcumin; Dose-Response Relationship, Drug; Estrogens; Female; Humans; Isoflavones; Pesticides; Receptors, Estrogen; Tumor Cells, Cultured

Curcumin and genistein are two natural products of plants obtained from Curcuma longa Linn (turmeric) and soybeans, respectively. Both compounds when present at micromolar concentrations are able to inhibit the growth of estrogen-positive human breast MCF-7 cells induced individually or by a mixture of the pesticides endosulfane, DDT and chlordane or 17-beta estradiol. When curcumin and genistein were added together to MCF-7 cells, a synergistic effect resulting in a total inhibition of the induction of MCF-7 cells by the highly estrogenic activity of endosulfane/chlordane/DDT mixtures was noted. These data suggest that the combination of curcumin and genistein in the diet have the potential to reduce the proliferation of estrogen-positive cells by mixtures of pesticides or 17-beta estradiol. Since it is difficult to remove pesticides completely from the environment or the diet and since both turmeric and soybeans are not toxic to humans, their inclusion in the diet in order to prevent hormone related cancers deserves consideration.

Topics: Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cell Division; Chlordan; Curcumin; DDT; Dieldrin; Drug Synergism; Endosulfan; Estradiol; Estrogens, Non-Steroidal; Female; Genistein; Humans; Isoflavones; Neoplasms, Hormone-Dependent; Pesticides; Tumor Cells, Cultured

Pharmacologically safe compounds that can inhibit the proliferation of tumor cells have potential as anticancer agents. Curcumin, a diferuloylmethane, is a major active component of the food flavor turmeric (Curcuma longa) that exhibits anticarcinogenic properties in vivo. In vitro, it suppressed c-jun/Ap-1 and NF-kappaB activation and type 1 human immunodeficiency virus long-terminal repeat-directed gene expression. We examined the antiproliferative effects of curcumin against several breast tumor cell lines, including hormone-dependent and -independent and multidrug-resistant (MDR) lines. Cell growth inhibition was monitored by [3H]thymidine incorporation, Trypan blue exclusion, crystal violet dye uptake and flow cytometry. All the cell lines tested, including the MDR-positive ones, were highly sensitive to curcumin. The growth inhibitory effect of curcumin was time- and dose-dependent, and correlated with its inhibition of ornithine decarboxylase activity. Curcumin preferentially arrested cells in the G2/S phase of the cell cycle. Curcumin-induced cell death was neither due to apoptosis nor to any significant change in the expression of apoptosis-related genes, including Bcl-2, p53, cyclin B and transglutaminase. Overall our results suggest that curcumin is a potent antiproliferative agent for breast tumor cells and may have potential as an anticancer agent.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Blotting, Western; Breast Neoplasms; Cell Cycle; Cell Division; Cell Line; Curcumin; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Humans; Ornithine Decarboxylase; Tetrazolium Salts; Thiazoles

An ethanol extract of turmeric ("Curcuma longa") as well as an ointment of curcumin (its active ingredient) were found to produce remarkable symptomatic relief in patients with external cancerous lesions. Reduction in smell were noted in 90% of the cases and reduction in itching in almost all cases. Dry lesions were observed in 70% of the cases, and a small number of patients (10%) had a reduction in lesion size and pain. In many patients the effect continued for several months. An adverse reaction was noticed in only one of the 62 patients evaluated.

Topics: Administration, Topical; Aged; Aged, 80 and over; Anti-Inflammatory Agents, Non-Steroidal; Breast Neoplasms; Catechols; Curcuma; Curcumin; Drug Evaluation; Female; Humans; Male; Middle Aged; Mouth Neoplasms; Odorants; Palliative Care; Plant Extracts; Pruritus; Skin Neoplasms; Skin Ulcer; Vulvar Neoplasms