curcumin and Colorectal-Neoplasms

Colorectal cancer (CRC) is one of the leading malignant diseases worldwide with a high rate of metastasis and poor prognosis. Treatment options include surgery, which is usually followed by chemotherapy in advanced CRC. With treatment, cancer cells could become resistant to classical cytostatic drugs such as 5-fluorouracil (5-FU), oxaliplatin, cisplatin, and irinotecan, resulting in chemotherapeutic failure. For this reason, there is a high demand for health-preserving re-sensitization mechanisms including the complementary use of natural plant compounds. Calebin A and curcumin, two polyphenolic turmeric ingredients derived from the Asian Curcuma longa plant, demonstrate versatile anti-inflammatory and cancer-reducing abilities, including CRC-combating capacity. After an insight into their epigenetics-modifying holistic health-promoting effects, this review compares functional anti-CRC mechanisms of multi-targeting turmeric-derived compounds with mono-target classical chemotherapeutic agents. Furthermore, the reversal of resistance to chemotherapeutic drugs was presented by focusing on calebin A's and curcumin's capabilities to chemosensitize or re-sensitize CRC cells to 5-FU, oxaliplatin, cisplatin, and irinotecan. Both polyphenols enhance the receptiveness of CRC cells to standard cytostatic drugs converting them from chemoresistant into non-chemoresistant CRC cells by modulating inflammation, proliferation, cell cycle, cancer stem cells, and apoptotic signaling. Therefore, calebin A and curcumin can be tested for their ability to overcome cancer chemoresistance in preclinical and clinical trials. The future perspective of involving turmeric-ingredients curcumin or calebin A as an additive treatment to chemotherapy for patients with advanced metastasized CRC is explained.

Topics: Cell Line, Tumor; Cisplatin; Colorectal Neoplasms; Curcumin; Cytostatic Agents; Drug Resistance, Neoplasm; Fluorouracil; Humans; Irinotecan; Oxaliplatin

The most common cancer-related cause of death worldwide is colorectal cancer. It is initiated with the formation of polyps, which further cause the development of colorectal cancer in multistep phases. Colorectal cancer mortality is high despite recent treatment breakthroughs and a greater understanding of its pathophysiology. Stress is one of the major causes of triggering different cellular signalling cascades inside the body and which might turn toward the development of cancer. Naturally occurring plant compounds or phytochemicals are being studied for medical purposes. Phytochemicals' benefits are being analyzed for inflammatory illnesses, liver failure, metabolic disorders, neurodegenerative disorders, and nephropathies. Cancer treatment with fewer side effects and better outcomes has been achieved by combining phytochemicals with chemotherapy. Resveratrol, curcumin, and epigallocatechin-3-gallate have been studied for their chemotherapeutic and chemopreventive potentiality, but hydrophobicity, solubility, poor bioavailability, and target selectivity limit the clinical uses of these compounds. The therapeutic potential is maximized by utilizing nanocarriers such as liposomes, micelles, nanoemulsions, and nanoparticles to increase phytochemical bioavailability and target specificity. This updated literature review discusses the clinical limitations, increased sensitivity, chemopreventive and chemotherapeutic effects, and the clinical limitations of the phytochemicals.

Topics: Biological Availability; Colorectal Neoplasms; Curcumin; Humans; Liposomes; Phytochemicals

There is growing concern in the rise of colorectal cancer (CRC) cases globally, and with this rise is the presentation of drug resistance. Like other cancers, current treatment options are either invasive or manifest severe side effects. Thus, there is a move towards implementing safer treatment options. Curcumin (CUR), extracted from Curcuma longa, has received significant attention by scientists as possible alternative to chemotherapeutic agents. It is safe and effective against CRC and nontoxic in moderate concentrations. Crucially, it specifically modulates apoptotic effects on CRC. However, the use of CUR is limited by its low solubility and poor bioavailability in aqueous media. These limitations are surmountable through novel approaches, such as nanoencapsulation of CUR, which masks the physicochemical properties of CUR, thus potentiating its anti-CRC effects. Furthermore, chemical derivatization of CUR is another approach that can be used to address the above constraints. This review spans published work in the last two decades, with key findings employing either of the two approaches, in addition to a combined approach in managing CRC. The combined approach affords the possibility of better treatment outcomes but not widely investigated nor yet clinically implemented.

Topics: Antineoplastic Agents; Biological Availability; Colorectal Neoplasms; Curcumin; Humans; Solubility

Colorectal cancer is one of the most common gastrointestinal malignancies, with high incidence rates, a low rate of early diagnosis, and complex pathogenesis. In recent years, there has been progress made in its diagnosis and treatment methods, but tumor malignant proliferation and metastasis after treatment still seriously affect the survival and prognosis of patients. Therefore, it is an extremely urgent task of current medicine to find new anti-tumor drugs with high efficiency and safety and low toxicity. Curcumin has shown potent anti-tumor and anti-inflammatory effects and is considered a hot spot in the research and development of anti-tumor drugs due to its advantages of precise efficacy, lower toxic side effects, and less drug resistance. Recent studies have revealed that curcumin has anti-tumor effects exerted on the epigenetic regulation of tumor-promoting/tumor-suppressing gene expression through the alteration of expression levels of non-coding RNAs (e.g., lncRNAs, miRNAs, and circRNAs). Herein, we summarize the interaction between curcumin and non-coding RNAs on the occurrence and development of colorectal cancer. The information complied in this review will serve as a scientific and reliable basis and viewpoint for the clinical application of non-coding RNAs in colorectal cancer.

Topics: Anti-Inflammatory Agents; Antineoplastic Agents; Biomarkers; Colorectal Neoplasms; Curcumin; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Humans; MicroRNAs; RNA, Circular; RNA, Long Noncoding

Colorectal cancer (CRC) is one of most common malignancies worldwide and its incidence is still growing. In spite of recent advances in targeted therapies, their clinical efficacy has been limited, non-curative and unaffordable. A growing body of literature indicates that CRC is a multi-modal disease, where a variety of factors within the tumor microenvironment play a significant role in its pathogenesis. For instance, imbalance in gut microbial profiles and impaired intestinal barrier function contribute to the overall intestinal inflammation and initiation of CRC. Moreover, persistent chronic inflammation favors a tumor microenvironment for the growth of cancer. In addition, autophagy or 'self-eating' is a surveillance mechanism involved in the degradation of cellular constituents that are generated under stressful conditions. Cancer stem cells (CSCs), on the other hand, engage in the onset of CRC and are able to endow cancer cells with chemo-resistance. Furthermore, the aberrant epigenetic alterations promote CRC. These evidences highlight the need for multi-targeted approaches that are not only safe and inexpensive but offer a more effective alternative to current generation of targeted drugs. Curcumin, derived from the plant Curcuma longa, represents one such option that has a long history of its use for a variety of chronic disease including cancer, in Indian ayurvedic and traditional Chinese medicine. Scientific evidence over the past few decades have overwhelmingly shown that curcumin exhibits a multitude of anti-cancer activities orchestrated through key signaling pathways associated with cancer. In this article, we will present a current update and perspective on this natural medicine - incorporating the basic cellular mechanisms it effects and the current state of clinical evidence, challenges and promise for its use as a cancer preventative and potential adjunct together with modern therapies for CRC patients.

Topics: Colorectal Neoplasms; Curcumin; Epigenomics; Humans; Inflammation; Signal Transduction; 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; 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

Colorectal cancer (CRC) is the second leading cause of cancer death worldwide and mostly affects men. Around 20% of its incidence is by familiar disposition due to hereditary syndromes. The CRC treatment involves surgery and chemotherapy; however, the side effects of treatments and the fast emergence of drug resistance evidence the necessity to find more effective drugs. Curcumin is the main polyphenol pigment present in Curcuma longa, a plant widely used as healthy food with antioxidant properties. Curcumin has synergistic effects with antineoplastics such as 5-fluorouracil and oxaliplatin, as well anti-inflammatory drugs by inhibiting cyclooxygenase-2 and the Nuclear factor kappa B. Furthermore, curcumin shows anticancer properties by inhibition of the Wnt/β-catenin, Hedgehog, Notch, and the phosphatidylinositol-3-kinase (PI3K)/Akt and the mammalian target of rapamycin (mTOR) signaling pathways implicated in the progression of CRC. However, the consumption of pure curcumin is less suitable, as the absorption is poor, and the metabolism and excretion are high. Pharmacological formulations and essential oils of the plant improve the curcumin absorption, resulting in therapeutical dosages. Despite the evidence obtained in vitro and in vivo, clinical studies have not yet confirmed the therapeutic potential of curcumin against CRC. Here we reviewed the last scientific information that supports the consumption of curcumin as an adjuvant for CRC therapy.

Topics: Adjuvants, Pharmaceutic; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Antioxidants; beta Catenin; Cell Line, Tumor; Chemotherapy, Adjuvant; Colorectal Neoplasms; Curcuma; Curcumin; Humans; NF-kappa B; Phosphatidylinositol 3-Kinase; Plant Extracts; Receptors, Notch; Signal Transduction; TOR Serine-Threonine Kinases

Colorectal cancer (CRC) is the second cause of cancer death worldwide. The metastatic disease is mainly treated with aggressive therapies consisting on combinations of cytotoxic chemotherapy plus anti-EGFR or anti-VEGF drugs. In spite of the improvements in clinical outcomes achieved in the last decade, these are the result of multiple new combinations using the existing therapeutic options and the introduction of regorafenib and TAS-102 in second or later lines of treatment. As immunotherapies are limited to less than 5% of CRC patients harboring tumors with deficient mismatch repair, there is an urgent need of finding new drugs to increase our patients' survival opportunities. Among all the natural products that are candidates to be used for the treatment of CRC cancer, curcumin (the golden spice) is in the spotlight. Used for centuries in the Ayurveda medicine, its demonstrated anticancer properties and low toxicity profile made it the focus of hundreds of preclinical and clinical investigations. So far we know that it can be combined with most of the aforementioned drugs in a safe and synergistic way. Regretfully, its poor bioavailability has been one of the main issues for its successful introduction in the clinic. Nevertheless, a plethora of new formulations with a huge increase in bioavailability are under study with promising results. In this review we discuss the possibility of incorporating curcumin in the treatment of CRC; specifically, we review preclinical and clinical data supporting its possible combination with current therapies as well as new formulations under clinical study. It is time for the golden spice revolution.

Topics: Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Curcumin; Humans

Curcumin, a naturally occurring polyphenol, possesses pleiotropic pharmacologic properties, including anti-inflammatory and anti-oxidant activities. Epidemiological evidence suggests that curcumin intake is associated with a reduced risk of Colorectal Cancer (CRC), highlighting the enormous potential of this botanical agent in the prevention and treatment of CRC.. We summarize the anticancer activity of curcumin and its derivatives in CRC.. We conducted a literature review on the therapeutic effects of curcumin and its derivatives in CRC.. In this review, a summary of the activities of curcumin in the treatment of CRC regarding its bioavailability, anticancer activity, modes of action, curcumin delivery systems have been provided based on the researches from preclinical experiments. Also, we discuss the therapeutic effects of curcumin derivatives in CRC. The human clinical trials that used curcumin or curcumin derivatives for the treatment of CRC are also highlighted here.. Curcumin possesses great potential as a chemopreventive agent in CRC. Moreover, emerging evidence reveals that it can be an effective adjuvant to CRC therapy. To date, few studies have explored the anticolon cancer activity of curcumin formulation and curcumin derivatives in vivo; therefore, more works are needed to confirm their effectiveness. In clinical trials, curcumin treatment protocols (formulation, dose, and duration) vary among studies. However, these trials consistently point out that the compound is well-tolerated and safe, albeit with little consensus on its therapeutic efficacy.

Topics: Antineoplastic Agents; Colorectal Neoplasms; Curcumin; Humans; Molecular Structure

Cancer treatment is improving widely over time, but finding a proper defender to beat them seems like a distant dream. The quest for identification and discovery of drugs with an effective action is still a vital work. The role of a membrane protein called P-glycoprotein, which functions as garbage chute that efflux the waste, xenobiotics, and toxins out of the cancer cells acts as a major reason behind the therapeutic failure of most chemotherapeutic drugs. In this review, we mainly focused on a multiple strategies by employing 5-Fluorouracil, curcumin, and lipids in Nano formulation for the possible treatment of colorectal cancer and its metastasis. Eventually, multidrug resistance and angiogenesis can be altered and it would be helpful in colorectal cancer targeting.We have depicted the possible way for the depletion of colorectal cancer cells without disturbing the normal cells. The concept of focusing on multiple pathways for marking the colorectal cancer cells could help in activating one among the pathways if the other one fails. The activity of the 5-Fluorouracil can be enhanced with the help of curcumin which acts as a chemosensitizer, chemotherapeutic agent, and even for altering the resistance. As we eat to survive, so do the cancer cells. The cancer cells utilize the energy source to stay alive and survive. Fatty acids can be used as the energy source and this concept can be employed for targeting the colorectal cancer cells and also for altering the resistant part.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily B, Member 1; Colorectal Neoplasms; Curcumin; Drug Synergism; Fluorouracil; Humans; Lipids; Nanoparticles; Prodrugs

Cancer is one of the life-taking diseases worldwide and among cancer-related death; colorectal cancer is the third most. Though conventional methods of treatment are available, multidrug resistance and side effects are predominant. Physicians and scientists are working side by side to develop an effective medicament, which is safe and cost-effective. However, most failures are obtained when focused on the clinical perspective. This review mainly brings out the correlation between the curcumin and its use for the mitigation of colorectal cancer, the use of curcumin as a chemotherapeutic agent, chemosensitizer, and in a combination and synergistic approach. The pharmacokinetics and pharmacodynamics properties of curcumin and its formulation approach helps in giving an idea to develop new approaches for the treatment of colorectal cancer using curcumin.

Topics: Antineoplastic Agents; Colorectal Neoplasms; Curcumin; Drug Resistance, Multiple; Humans

Curcumin, an herbal naturally occurring polyphenol, has recently been proposed for the treatment of neurodegenerative, neurological and cancer diseases due to its pleiotropic effect. Recent studies indicated that dysbiosis is associated with the abovementioned and other diseases, and gut microflora may be a new potential therapeutic target. The new working hypothesis that could explain the curative role of curcumin, despite its limited availability, is that curcumin acts indirectly on the brain, affecting the "gut-brain-microflora axis", a complex two-way system in which the gut microbiome and its composition, are factors that preserve and determine brain health. It is therefore suspected that curcumin and its metabolites have a direct regulatory effect on gut microflora and vice versa, which may explain the paradox between curcumin's poor bioavailability and its commonly reported therapeutic effects. Curcumin and its metabolites can have health benefits by eliminating intestinal microflora dysbiosis. In addition, curcumin undergoes enzymatic modifications by bacteria, forming pharmacologically more active metabolites than their parent, curcumin. In this review, we summarize a number of studies that highlight the interaction between curcumin and gut microbiota and vice versa, and we consider the possibility of microbiome-targeted therapies using curcumin, particularly in disease entities currently without causal treatment.

Topics: Antineoplastic Agents; Bacteria; Brain; Colorectal Neoplasms; Curcumin; Dysbiosis; Gastrointestinal Microbiome; Humans; Intestines

Curcumin diffuses through cell membranes into the endoplasmic reticulum, mitochondria, and nucleus, where it exerts actions, as an antioxidant property. Therefore, its use has been advocated for chemopreventive, antimetastatic, and anti-angiogenic purposes. We conducted a literature review to summarize studies investigating the relationship between curcumin and colorectal cancer (CRC). In vitro studies, performed on human colon cancer cell lines, showed that curcumin inhibited cellular growth through cycle arrest at the G2/M and G1 phases, as well as stimulated apoptosis by interacting with multiple molecular targets. In vivo studies have been performed in inflammatory and genetic CRC animal models with a chemopreventive effect. To improve curcumin bioavailability, it has been associated with small particles that increase its absorption when orally administered with excellent results on both inflammation and carcinogenesis. Curcumin has been used, moreover, as a component of dietetic formulations for CRC chemoprevention. These combinations showed in vitro and in vivo anticarcinogenetic properties in inflammation-related and genetic CRC. A synergic effect was suggested using an individual constituent dosage, which was lower than that experimentally used "in vivo" for single components. In conclusion, curcumin falls within the category of plant origin substances able to prevent CRC in animals. This property offers promising expectations in humans.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Clinical Studies as Topic; Colorectal Neoplasms; Curcumin; Dietary Supplements; Disease Models, Animal; Drug Compounding; Drug Evaluation, Preclinical; Humans; Translational Research, Biomedical

Colorectal cancer (CRC) ranks second for incidence in females (third in males). Currently, a broad spectrum of treatment options exists for the treatment of colorectal tumors. However, existing therapeutic options often lead to trauma, side effects, and high cost. Hence, there is an ongoing quest to detect novel approaches for the treatment of colon cancer. Recently, multiple studies have reported that consuming functional foods that are loaded with natural compounds can prevent the risk of CRC. In this review, the authors have attempted to collect information about the best possible foods and their active ingredients that may be used in treatment. Information retrieved through research reveals that all functional foods have aroma, taste, and nutritive value along with active ingredients that are beneficial for human health. For instance, the consumption of red meat increases CRC risk; on the other hand, the consumption of fresh vegetables diminishes such risk. Additionally, plant-based diets comprise fibers, bioactive compounds, and micronutrients, which are reported to have antioxidant as well as anticancer properties. Bioactively rich functional foods have been reported to provide protection against CRC. However, few active components like curcumin work in a dose-dependent manner. Thus, the involvement of medical practitioners during a clinical trial is highly recommended. In general, these active dietary components may aid in improving the health and well-being of patients as well as in managing the risk associated with cancer in a more comprehensive way.

Topics: Colorectal Neoplasms; Curcumin; Folic Acid; Functional Food; Garlic; Humans; Signal Transduction

Phytochemicals are derived from natural sources and identified to be the potential inhibitors of colorectal cancer (CRC) progression. Phytochemicals are also recognized as inhibitors of hallmarks of cancer such as invasion, migration, proliferation, angiogenesis, tumor escape immune surveillance, metastasis, etc. Phytochemicals are safe and effective drugs that are known to be associated with suppressing CRC growth and metastasis. All these accumulated evidences of phytochemicals address crucial mechanisms of CRC growth and metastasis and represent worthy consideration towards developing effective therapies. This review is focused on the functions of the most promising phytochemicals and their derivatives as potential key players that effectively target CRC progression.

Topics: Cell Proliferation; Colorectal Neoplasms; Curcumin; Humans; Lycopene; Neoplasm Metastasis; Phytochemicals; Polyphenols; Tea

Colorectal cancer is the third important cause of cancer-associated deaths across the world. Hence, there is an urgent need for understanding the complete mechanism associated with colorectal cancer, which in turn can be utilized toward early detection as well as the treatment of colorectal cancer in humans. Though colorectal cancer is a complex process and chemotherapy is the first step toward the treatment of colorectal cancer, recently several studies suggested that dietary phytochemicals may also aid significantly in reducing colorectal cancer risk in human. However, only few phytochemicals, specifically curcumin derived from the rhizomes of Curcuma longa, have better chemotherapeutic property, which might be because of its ability to regulate the activity of key factors associated with the initiation, promotion, as well as progression of tumors.. In the present review, the authors made an attempt to summarize the physiochemical properties of curcumin, which in turn prevent colorectal cancer via regulating numerous cell signaling as well as genetic pathways.. Accumulated evidence suggested that curcumin suppresses tumour/colon cancer in various ways, (a) restricting cell cycle progression, or stimulating apoptosis, (b) restricting angiogenesis, anti-apoptotic proteins expression, cell survival signaling pathways & their cross-communication and (c) regulating immune responses. The information discussed in the present review will be useful in the drug discovery process as well as the treatment and prevention of colorectal cancer in humans.

Topics: Antineoplastic Agents; Colorectal Neoplasms; Curcuma; Curcumin; Humans; Plant Extracts; Signal Transduction

Colorectal cancer (CRC) is among the top three cancer with higher incident and mortality rate worldwide. It is estimated that about over than 1.1 million of death and 2.2 million new cases by the year 2030. The current treatment modalities with the usage of chemo drugs such as FOLFOX and FOLFIRI, surgery and radiotherapy, which are usually accompanied with major side effects, are rarely cured along with poor survival rate and at higher recurrence outcome. This trigger the needs of exploring new natural compounds with anti-cancer properties which possess fewer side effects. Curcumin, a common spice used in ancient medicine was found to induce apoptosis by targeting various molecules and signaling pathways involved in CRC. Disruption of the homeostatic balance between cell proliferation and apoptosis could be one of the promoting factors in colorectal cancer progression. In this review, we describe the current knowledge of apoptosis regulation by curcumin in CRC with regard to molecular targets and associated signaling pathways.

Topics: Cell Line, Tumor; Cell Proliferation; Cell Survival; Colorectal Neoplasms; Curcumin; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Humans; Signal Transduction

Colorectal cancer (CRC) therapy using conventional chemotherapeutics represents a considerable burden for the patient's organism because of high toxicity while the response is relatively low. Our review summarizes the findings about natural compounds as chemoprotective agents for decreasing risk of CRC. It also identifies natural compounds which possess anti-tumor effects of various characteristics, mainly in vitro on colorectal cell lines or in vivo studies on experimental models, but also in a few clinical trials. Many of natural compounds suppress proliferation by inducing cell cycle arrest or induce apoptosis of CRC cells resulting in the inhibition of tumor growth. A novel employment of natural substances is a so-called combination therapy - administration of two or more substances - conventional chemotherapeutics and a natural compound or more natural compounds at a time. Some natural compounds may sensitize to conventional cytotoxic therapy, reinforce the drug effective concentration, intensify the combined effect of both administered therapeutics or exert cytotoxic effects specifically on tumor cells. Moreover, combined therapy by targeting multiple signaling pathways, uses various mechanisms to reduce the development of resistance to antitumor drugs. The desired effect could be to diminish burden on the patient's organism by replacing part of the dose of a conventional chemotherapeutic with a natural substance with a defined effect. Many natural compounds are well tolerated by the patients and do not cause toxic effects even at high doses. Interaction of conventional chemotherapeutics with natural compounds introduces a new aspect in the research and therapy of cancer. It could be a promising approach to potentially achieve improvements, while minimizing of adverse effects associated with conventional chemotherapy.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Biological Products; Cell Proliferation; Colorectal Neoplasms; Dose-Response Relationship, Drug; Humans; Molecular Structure; Structure-Activity Relationship

Colorectal cancer (CRC) is the third most common cause of cancer-related deaths worldwide. Hence there is a need to identify new therapeutic agents that improve the current repertoire of chemotherapeutic drugs. The antitumor activity of curcumin has been reported for several tumors, including CRC. A recent phase I trial showed that curcumin is safe and tolerable adjunct to FOLFOX (5-fluorouracil, folinic acid and oxaliplatin) chemotherapy in patient-derived colorectal liver metastases at doses up to 2 g daily. Another trial revealed the effect of combining curcumin with FOLFOX in patients with inoperable colorectal cancer. The aim of current review was to summarize the current knowledge about possible molecular mechanisms of curcumin in CRC with particular emphasis on preclinical and early clinical studies of colorectal cancer.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Curcumin; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Organoplatinum Compounds

Colorectal cancer (CRC) is one of the most common causes of cancer-associated mortality in the world. Anti-tumor effect of curcumin has been shown in different cancers; however, the therapeutic potential of novel phytosomal curcumin, as well as the underlying molecular mechanism in CRC, has not yet been explored.. The anti-proliferative, anti-migratory and apoptotic activity of phytosomal curcumin in CT26 cells was assessed by MTT assay, wound healing assay and Flow cytometry, respectively. Phytosomal curcumin was also tested for its in-vivo activity in a xenograft mouse model of CRC. In addition, oxidant/antioxidant activity was examined by DCFH-DA assay in vitro, measurement of malondialdehyde (MDA), Thiol and superoxidedismutase (SOD) and catalase (CAT) activity and also evaluation of expression levels of Nrf2 and GCLM by qRT-PCR in tumor tissues. In addition, the effect of phytosomal curcumin on angiogenesis was assessed by the measurement of VEGF-A and VEGFR-1 and VEGF signaling regulatory microRNAs (miRNAs) in tumor tissue.. Phytosomal curcumin exerts anti-proliferative, anti-migratory and apoptotic activity in-vitro. It also decreases tumor growth and augmented 5-fluorouracil (5-FU) anti-tumor effect in-vivo. In addition, our data showed that induction of oxidative stress and inhibition of angiogenesis through modulation of VEGF signaling regulatory miRNAs might be underlying mechanisms by which phytosomal curcumin exerted its antitumor effect.. Our data confirmed this notion that phytosomal curcumin administrates anticancer effects and can be used as a complementary treatment in clinical settings.

Topics: Animals; Antineoplastic Agents; Cell Proliferation; Colorectal Neoplasms; Curcumin; Humans; Mice; Neovascularization, Pathologic; Oxidative Stress; Signal Transduction

The aim of this study was to review the literature to assess if there is evidence to support the use of Curcumin as a safe complementary therapy in treating Crohn's Disease (CD) in conjunction with Remicade.. Systematic searches were performed by three researchers using electronic databases (ProQuest Medical Library, CINAHL Complete, and PUBMED) to locate and identify articles to meet a predetermined set of inclusion criteria. Specifically full text, peer-reviewed articles published after 2007 were included if they studied human participants 18 years or older.. Tumor necrosis factor-alpha (TNF-a) and Interleukin-1 (IL-1) levels increase in CD patients. Remicade reduces TNF-a in adults with CD. The issues are eventual loss of response (LOR) once IL-1 increases, and severe risks such as malignancy. CD patients using Curcumin saw a 55 point mean reduction in the Crohn's Disease Activity Index, reducing IL-1 and Crp. Plus it reduced TNF-a and PPMTase which improved colorectal cancer outcomes.. LOR of Remicade occurs when IL-1 increases, and it can cause malignancy. Research shows Curcumin reduces IL-1 and improves cancer outcomes. Future research, using both Remicade and Curcumin, would have to be done, but preliminary data would suggest using both would reduce LOR. Curcumin, even by itself, was found to be a cheap and safe way to reduce CD symptoms and inflammatory markers.

Topics: Anti-Inflammatory Agents; Colorectal Neoplasms; Crohn Disease; Curcuma; Curcumin; Humans; Infliximab; Interleukin-1; Phytotherapy; Plant Extracts; Tumor Necrosis Factor-alpha

Topics: Animals; Antineoplastic Agents, Phytogenic; Biomarkers, Tumor; Colorectal Neoplasms; Curcumin; Gene Expression Regulation, Neoplastic; Humans; MicroRNAs; Treatment Outcome

Wnt/β-catenin pathway is one of the main/frequent dysregulated pathways in several tumor types, including colon cancer. Aberrant activation of this pathway is associated with cell proliferation, invasive behaviors, and cell resistance, suggesting its potential value as a therapeutic target in treatment of CRC. Several agents have been developed for targeting of this pathway (e.g, natural agents: curcumin, 3,3-diindolylmethane, phytoestrogen; Synthetic/small Wnt inhibitors: Rofecoxib; PRI-724, CWP232291; and monoclonal antibody against frizzled receptors, Vanituctumab). This review summarizes the current knowledge about the therapeutic potential of targeting Wnt pathway with particular emphasis on preclinical/clinical studies in treatment of colorectal cancer. J. Cell. Biochem. 118: 1979-1983, 2017. © 2017 Wiley Periodicals, Inc.

Topics: Animals; Antineoplastic Agents; beta Catenin; Bridged Bicyclo Compounds, Heterocyclic; Cell Proliferation; Colorectal Neoplasms; Curcumin; Gene Expression Regulation, Neoplastic; Humans; Indoles; Lactones; Molecular Targeted Therapy; Pyrimidinones; Signal Transduction; Sulfones; Wnt Proteins

The International Agency for Research on Cancer recently released an assessment classifying red and processed meat as "carcinogenic to humans" on the basis of the positive association between increased consumption and risk for colorectal cancer. Diet, however, can also decrease the risk for colorectal cancer and be used as a chemopreventive strategy. Bioactive dietary molecules, such as n-3 polyunsaturated fatty acids, curcumin, and fermentable fiber, have been proposed to exert chemoprotective effects, and their molecular mechanisms have been the focus of research in the dietary/chemoprevention field. Using these bioactives as examples, this review surveys the proposed mechanisms by which they exert their effects, from the nucleus to the cellular membrane. In addition, we discuss emerging technologies involving the culturing of colonic organoids to study the physiological effects of dietary bioactives. Finally, we address future challenges to the field regarding the identification of additional molecular mechanisms and other bioactive dietary molecules that can be utilized in our fight to reduce the incidence of colorectal cancer.

Topics: Animals; Anticarcinogenic Agents; Colonic Neoplasms; Colorectal Neoplasms; Curcumin; Diet, Healthy; Dietary Fiber; DNA Methylation; Epigenesis, Genetic; Fatty Acids, Omega-3; Fermentation; Gastrointestinal Microbiome; Gene Expression Regulation; Gene Expression Regulation, Neoplastic; Histones; Humans; MicroRNAs; Models, Biological; Nutrigenomics; Protein Processing, Post-Translational

Colorectal cancer (CRC) is a type of cancer with high morbidity and mortality rates worldwide and has become a global health problem. The conventional radiotherapy and chemotherapy regimen for CRC not only has a low cure rate but also causes side effects. Many studies have shown that adequate intake of fruits and vegetables in the diet may have a protective effect on CRC occurrence, possibly due to the special biological protective effect of the phytochemicals in these foods. Numerous in vitro and in vivo studies have demonstrated that phytochemicals play strong antioxidant, anti-inflammatory and anti-cancer roles by regulating specific signaling pathways and molecular markers to inhibit the occurrence and development of CRC. This review summarizes the progress on CRC prevention using the phytochemicals sulforaphane, curcumin and resveratrol, and elaborates on the specific underlying mechanisms. Thus, we believe that phytochemicals might provide a novel therapeutic approach for CRC prevention, but future clinical studies are needed to confirm the specific preventive effect of phytochemicals on cancer.

Topics: Animals; Anticarcinogenic Agents; Apoptosis; Cell Cycle Checkpoints; Colorectal Neoplasms; Curcumin; Humans; Neovascularization, Pathologic; NF-E2-Related Factor 2; Phytochemicals; Resveratrol; Stilbenes

Colorectal cancer (CRC) remains a major cause of cancer death worldwide. Over 70% of CRC cases are sporadic and related to lifestyle. Epidemiological studies inversely correlate CRC incidence with the intake of fruits and vegetables but not with their phenolic content. Preclinical studies using in vitro (cell lines) and animal models of CRC have reported anticancer effects for dietary phenolics through the regulation of different markers and signaling pathways. Herein, we review and contrast the evidence between preclinical studies and clinical trials (patients with CRC or at risk, familial adenopolyposis or aberrant crypt foci) investigating the protective effects of curcumin, resveratrol, isoflavones, green tea extracts (epigallocatechin gallate), black raspberry powder (anthocyanins and ellagitannins), bilberry extract (anthocyanins), ginger extracts (gingerol derivatives), and pomegranate extracts (ellagitannins and ellagic acid). To date, curcumin is the most promising polyphenol as possible future adjuvant in CRC management. Overall, the clinical evidence of dietary phenolics against CRC is still weak and the amounts needed to exert some effects largely exceed common dietary doses. We discuss here the possible reasons behind the gap between preclinical and clinical research (inconsistence of results, lack of clinical endpoints, etc.), and provide an outlook and a roadmap to approach this topic.

Topics: Animals; Antineoplastic Agents, Phytogenic; Clinical Trials as Topic; Colorectal Neoplasms; Curcumin; Diet; Drug Screening Assays, Antitumor; Gastrointestinal Microbiome; Humans; Lythraceae; Phenols; Resveratrol; Stilbenes; Tea; Zingiber officinale

The strong link between inflammation and colorectal carcinogenesis provides the rationale for using anti-inflammatory agents for chemoprevention of colorectal cancer (CRC). Several naturally occurring substances with anti-inflammatory properties, used in a purified 'nutraceutical' form, including omega-3 polyunsaturated fatty acids (PUFAs) such as eicosapentaenoic acid (EPA) and polyphenols such as curcumin and resveratrol, have been demonstrated to have anti-CRC activity in preclinical models. As expected, these agents have an excellent safety and tolerability profile in Phase II clinical trials. Phase III randomized clinical trials of these naturally occurring substances are now beginning to be reported. The omega-3 polyunsaturated fatty acid EPA, in the free fatty acid (FFA) form, has been demonstrated to reduce adenomatous polyp number and size in patients with familial adenomatous polyposis (FAP), a finding which has prompted evaluation of this formulation of EPA for prevention of 'sporadic' colorectal neoplasia. Anti-inflammatory 'nutraceuticals' require further clinical evaluation in polyp prevention trials as they exhibit many of the characteristics of the ideal cancer chemoprevention agent, including safety, tolerability and patient acceptability.

Topics: Anti-Inflammatory Agents; Anticarcinogenic Agents; Colorectal Neoplasms; Curcumin; Dietary Supplements; Fatty Acids, Omega-3; Humans; Resveratrol; Stilbenes; Vitamin D

Curcumin, a polyphenol and derivative of turmeric is one of the most commonly used and highly researched phytochemicals. Several research studies have provided interesting insights into the multiple mechanisms by which curcumin may mediate chemotherapy and chemopreventive effects on cancers, including colorectal cancer. Curcumin has the ability to inhibit carcinogenic promotion of colorectal cancer through the modulation of multiple molecular targets such as transcription factors, enzymes, cell cycle proteins, cell surface adhesion proteins, survival pathways and cytokines. A number of clinical trials dealing with curcumin's efficacy and safety revealed poor absorption and low bioavailability. Different factors contributing to the low bioavailability include low plasma level, tissue distribution, rapid metabolism and elimination from the body. Although, curcumin poor absorption and low systemic bioavailability limit its translation into clinics, some of the methods for its use can be approached to enhance the absorption and achieve a therapeutic level of curcumin. Recent clinical trials suggest a potential role for curcumin in regards to colorectal cancer therapy.

Topics: Animals; Antineoplastic Agents, Phytogenic; Biological Availability; Colorectal Neoplasms; Curcumin; Evidence-Based Medicine; Humans; Signal Transduction; Treatment Outcome

Colorectal cancer (CRC) is a second leading cause of cancer deaths in the Western world. Currently there is no effective treatment except resection at a very early stage with or without chemotherapy. Of various epithelial cancers, CRC in particular has a potential for prevention, since most cancers follow the adenoma-carcinoma sequence, and the interval between detection of an adenoma and its progression to carcinoma is usually about a decade. However no effective chemopreventive agent except COX-2 inhibitors, limited in their scope due to cardiovascular side effects, have shown promise in reducing adenoma recurrence. To this end, natural agents that can target important carcinogenic pathways without demonstrating discernible adverse effects would serve as ideal chemoprevention agents. In this review, we discuss merits of two such naturally occurring dietary agents-curcumin and resveratrol-for chemoprevention of CRC.

Topics: Animals; Anticarcinogenic Agents; Clinical Trials as Topic; Colorectal Neoplasms; Curcumin; Humans; Resveratrol; Stilbenes

Despite the use of surgical resection and aggressive chemotherapy, nearly 50% of patients with colorectal carcinoma develop recurrent disease, highlighting the need for improved therapies. Curcumin (diferuloylmethane), the major active ingredient of turmeric (curcuma longa) with no discernable toxicity, has been shown to inhibit the growth of transformed cells and colon carcinogenesis at the initiation, promotion, and progression stages in carcinogen-induced rodent models. In a Phase I clinical trial, curcumin has been found to be extremely well tolerated and effective. In this review, we summarized the current status of our knowledge about the effectiveness of curcumin when given in combination with current chemotherapeutics such as 5-fluorouracil, oxaliplatin, and gemcitabine in treatment of gastrointestinal cancers with particular reference to colorectal cancer. Existing data suggest that curcumin in combination with chemotherapy is a superior strategy for treatment of gastrointestinal cancer.

Topics: Adenoma; Animals; Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Colorectal Neoplasms; Curcumin; Deoxycytidine; Fluorouracil; Gastrointestinal Neoplasms; Gemcitabine; Humans; Organoplatinum Compounds; Oxaliplatin; Treatment Outcome

Curcumin is a polyphenol derived from Curcuma longa. Over the last few years, a number of studies have provided evidence of its main pharmacological properties including chemosensitizing, radiosensitizing, wound healing activities, antimicrobial, antiviral, antifungical, immunomodulatory, antioxidant and anti-inflammatory. More recent data provide interesting insights into the effect of this compound on cancer chemoprevention and chemotherapy. In fact, preclinical studies have shown its ability to inhibit carcinogenesis in various types of cancer including colorectal cancer (CRC). Curcumin has the capacity of interact with multiple molecular targets affecting the multistep process of carcinogenesis. Also, curcumin is able to arrest the cell cycle, to inhibit the inflammatory response and the oxidative stress and to induce apoptosis in cancer cells. Likewise, it has been shown to possess marked antiangiogenic properties. Furthermore, curcumin potentiates the growth inhibitory effect of cyclo-oxygenase (COX)-2 inhibitors and traditional chemotherapy agents implicating another promising therapy regimen in the future treatment of CRC. However, its clinical advance has been hindered by its short biological half-life and low bioavailability after oral administration. This review is intended to provide the reader an update of the bioavailability and pharmacokinetics of curcumin and describes the recently identified molecular pathways responsible of its anticancer potential in CRC.

Topics: Animals; Anticarcinogenic Agents; Antineoplastic Agents; Cell Cycle; Clinical Trials as Topic; Colorectal Neoplasms; Curcumin; Disease Models, Animal; Humans; Mice; Rats; Wound Healing

Celecoxib (Celebrex, Pfizer, NY, USA) is a worldwide top branded COX-2-specific inhibitor. It was shown to provide relief of arthritic pain and inflammation and has recently been under investigation for the prevention and treatment of cancer. However, recent studies showed that long term use of high doses of celecoxib is associated with an increased cardiovascular toxicity. We discovered that the addition of curcumin, a natural COX-2 inhibitor, to celecoxib synergistically (up to 1000%) augments the growth inhibitory effects of celecoxib in in-vitro and in-vivo models of arthritis and cancer, thus rendering effective action of the drug at up to tenfold lower dose. This may pave the way for a novel strategy to treat arthritis and cancer because its effect [1] can be achieved in the serum of patients receiving standard anti inflammatory or anti-neoplastic dosages of celecoxib, and [2] involves a regimen with a very low profile of side effects. Preliminary data suggest that the combination is not limited only to celecoxib and that addition of curcumin to other NSAIDs such as sulindac, synergistically augments neoplastic cell growth inhibition. Based on these finding we received an IRB approval to evaluate celecoxib+curcumin in patients with osteoarthritis, pancreatic cancer and metastatic CRC. We hope to complete these novel human clinical trials, in 12-18 months.

Topics: Apoptosis; Celecoxib; Cell Proliferation; Colorectal Neoplasms; Curcumin; Cyclooxygenase 2 Inhibitors; Dinoprostone; Drug Synergism; Drug Therapy, Combination; Humans; Osteoarthritis; Pancreatic Neoplasms; Pyrazoles; Sulfonamides

Curcumin has long been expected to be a therapeutic or preventive agent for several major human diseases because of its antioxidative, anti-inflammatory, and anticancerous effects. In phase I clinical studies, curcumin with doses up to 3600-8000 mg daily for 4 months did not result in discernible toxicities except mild nausea and diarrhea. The pharmacokinetic studies of curcumin indicated in general a low bioavailability of curcumin following oral application. Nevertheless, the pharmacologically active concentration of curcumin could be achieved in colorectal tissue in patients taking curcumin orally and might also be achievable in tissues such as skin and oral mucosa, which are directly exposed to the drugs applied locally or topically. The effect of curcumin was studied in patients with rheumatoid arthritis, inflammatory eye diseases, inflammatory bowel disease, chronic pancreatitis, psoriasis, hyperlipidemia, and cancers. Although the preliminary results did support the efficacy of curcumin in these diseases, the data to date are all preliminary and not conclusive. It is imperative that well-designed clinical trials, supported by better formulations of curcumin or novel routes of administration, be conducted in the near future.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Biological Availability; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Colorectal Neoplasms; Curcumin; Dose-Response Relationship, Drug; Drug Administration Schedule; Forecasting; Humans; Inflammatory Bowel Diseases; Neoplasm Metastasis; Precancerous Conditions; Psoriasis; Tissue Distribution

Colorectal cancer is one of the leading causes of cancer deaths in the Western world. More than 56,000 newly diagnosed colorectal cancer patients die each year in the United States. Available therapies are either not effective or have unwanted side effects. Epidemiological data suggest that dietary manipulations play an important role in the prevention of many human cancers. Curcumin the yellow pigment in turmeric has been widely used for centuries in the Asian countries without any toxic effects. Epidemiological data also suggest that curcumin may be responsible for the lower rate of colorectal cancer in these countries. Curcumin is a naturally occurring powerful anti-inflammatory medicine. The anticancer properties of curcumin have been shown in cultured cells and animal studies. Curcumin inhibits lipooxygenase activity and is a specific inhibitor of cyclooxygenase-2 expression. Curcumin inhibits the initiation of carcinogenesis by inhibiting the cytochrome P-450 enzyme activity and increasing the levels of glutathione-S-transferase. Curcumin inhibits the promotion/progression stages of carcinogenesis. The anti-tumor effect of curcumin has been attributed in part to the arrest of cancer cells in S, G2/M cell cycle phase and induction of apoptosis. Curcumin inhibits the growth of DNA mismatch repair defective colon cancer cells. Therefore, curcumin may have value as a safe chemotherapeutic agent for the treatment of tumors exhibiting DNA mismatch repair deficient and microsatellite instable phenotype. Curcumin should be considered as a safe, non-toxic and easy to use chemotherapeutic agent for colorectal cancers arise in the setting of chromosomal instability as well as microsatellite instability.

Topics: Anti-Inflammatory Agents; Antineoplastic Agents; Base Pair Mismatch; Colorectal Neoplasms; Curcumin; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Humans; Isoenzymes; Membrane Proteins; Prostaglandin-Endoperoxide Synthases

Colorectal cancer prevention is crucial for public health, given its high mortality rates, particularly in young adults. The early detection and treatment of precancerous lesions is key to preventing carcinogenesis progression. Natural compounds like curcumin and anthocyanins show promise in impeding adenomatous polyp progression in preclinical models. We conducted a randomized, double-blind, placebo-controlled, phase II presurgical trial in 35 patients with adenomatous polyps to explore the biological effects of curcumin and anthocyanins on circulating biomarkers of inflammation and metabolism. No significant difference in biomarker changes by treatment arm was observed. However, the network analysis before treatment revealed inverse correlations between adiponectin and BMI and glycemia, as well as direct links between inflammatory biomarkers and leptin and BMI. In addition, a considerable inverse relationship between adiponectin and grade of dysplasia was detected after treatment (corr = -0.45). Finally, a significant increase in IL-6 at the end of treatment in subjects with high-grade dysplasia was also observed (

Topics: Adenoma; Adiponectin; Anthocyanins; Biomarkers; Carcinogenesis; Colorectal Neoplasms; Curcumin; Humans; Hyperplasia; Inflammation; Young Adult

Colorectal cancer is the third most common cancer and accounts for the second highest number of cancer-related deaths worldwide. Natural products such as the turmeric-derived curcuminoids are known to have protective effects against several kinds of cancers by acting as antioxidant and anti-inflammatory agents. Here, we present a protocol for assessing the effects of curcuminoids on serum cytokine profiles in a double-blind placebo-controlled trial of patients with stage 3 colorectal cancer undergoing chemotherapy. The protocol could also be applied to other cancer types.

Topics: Anti-Inflammatory Agents; Colorectal Neoplasms; Curcuma; Diarylheptanoids; Humans; Randomized Controlled Trials as Topic

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

Curcumin is the main active ingredient of the spice turmeric, investigated extensively for putative anticancer properties.. This phase IIa open-labelled randomized controlled trial aimed to assess safety, efficacy, quality of life, neurotoxicity, curcuminoids, and C-X-C-motif chemokine ligand 1 (CXCL1) in patients receiving folinic acid/5-fluorouracil/oxaliplatin chemotherapy (FOLFOX) compared with FOLFOX + 2 g oral curcumin/d (CUFOX).. Twenty-eight patients aged >18 y with a histological diagnosis of metastatic colorectal cancer were randomly assigned (1:2) to receive either FOLFOX or CUFOX. Safety was assessed by Common Toxicity Criteria-Adverse Event reporting, and efficacy via progression-free survival (PFS) and overall survival (OS). Quality of life and neurotoxicity were assessed using questionnaires (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 and Functional Assessment of Cancer Treatment-Gynecologic Oncology Group-Neurotoxicity). Plasma curcuminoids were determined with liquid chromatography (LC) electrospray ionization tandem mass spectrometry and CXCL1 by ELISA.. Addition of daily oral curcumin to FOLFOX chemotherapy was safe and tolerable (primary outcome). Similar adverse event profiles were observed for both arms. In the intention-to-treat population, the HR for PFS was 0.57 (95% CI: 0.24, 1.36; P = 0.2) (median of 171 and 291 d for FOLFOX and CUFOX, respectively) and for OS was 0.34 (95% CI: 0.14, 0.82; P = 0.02) (median of 200 and 502 d for FOLFOX and CUFOX, respectively). There was no significant difference between arms for quality of life (P = 0.248) or neurotoxicity (P = 0.223). Curcumin glucuronide was detectable at concentrations >1.00 pmol/mL in 15 of 18 patients receiving CUFOX. Curcumin did not significantly alter CXCL1 over time (P = 0.712).. Curcumin is a safe and tolerable adjunct to FOLFOX chemotherapy in patients with metastatic colorectal cancer. This trial was registered at clinicaltrials.gov as NCT01490996 and at www.clinicaltrialsregister.eu as EudraCT 2011-002289-19.

Topics: Administration, Oral; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Curcumin; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Treatment Outcome

Familial adenomatous polyposis is an autosomal dominant disorder characterized by the development of hundreds of colorectal adenomas and eventually colorectal cancer. Oral administration of the spice curcumin has been followed by regression of polyps in patients with this disorder. We performed a double-blinded randomized trial to determine the safety and efficacy of curcumin in patients with familial adenomatous polyposis.. This study included 44 patients with familial adenomatous polyposis (18-85 years old) who had not undergone colectomy or had undergone colectomy with ileorectal anastomosis or ileal anal pouches, had at least 5 intestinal adenomatous polyps, and had enrolled in Puerto Rico or the United States from September 2011 through November 2016. Patients were randomly assigned (1:1) to groups given 100% pure curcumin (1,500 mg orally, twice per day) or identical-appearing placebo capsules for 12 months. The number and size of lower gastrointestinal tract polyps were evaluated every 4 months for 1 year. The primary outcome was the number of polyps in the curcumin and placebo groups at 12 months or at the time of withdrawal from the study according to the intention-to-treat principle.. After 1 year of treatment, the average rate of compliance was 83% in the curcumin group and 91% in the placebo group. After 12 weeks, there was no significant difference in the mean number of polyps between the placebo group (18.6; 95% CI, 9.3-27.8) and the curcumin group (22.6; 95% CI, 12.1-33.1; P = .58). We found no significant difference in mean polyp size between the curcumin group (2.3 mm; 95% CI, 1.8-2.8) and the placebo group (2.1 mm; 95% CI, 1.5-2.7; P = .76). Adverse events were few, with no significant differences between groups.. In a double-blinded randomized trial of patients with familial adenomatous polyposis, we found no difference in the mean number or size of lower intestinal tract adenomas between patients given curcumin 3,000 mg/day and those given placebo for 12 weeks. Clinicaltrials.gov ID NCT00641147.

Topics: Adenoma; Adenomatous Polyposis Coli; Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Colorectal Neoplasms; Curcumin; Double-Blind Method; Female; Humans; Male; Middle Aged; Treatment Outcome; Young Adult

The need for low toxicity adjuncts to standard care chemotherapy in inoperable colorectal cancer, with potential to improve outcomes and decrease the side-effect burden, is well recognised. Addition of the low toxicity diet-derived agent, curcumin (the active ingredient of turmeric), to standard oxaliplatin-based therapy has shown promise in numerous pre-clinical studies.. This study is the first to combine daily oral curcumin with standard care FOLFOX-based (5-fluorouracil, folinic acid and oxaliplatin) chemotherapy in colorectal cancer patients with inoperable liver metastases: the CUFOX trial. CUFOX comprises a Phase 1 dose-escalation study (3 + 3 + 3 design) to determine an acceptable target dose of curcumin with which to safely proceed to a Phase IIa open-labelled randomised controlled trial. Thirty three participants with histological or cytological confirmation of inoperable colorectal cancer will then be randomised to oxaliplatin-based chemotherapy with the addition of daily oral curcumin at the target dose determined in Phase I, or to standard care oxaliplatin-based chemotherapy alone (recruiting at a ratio of 2:1).. Primary outcome measures will be the determination of a target dose which is both safe and tolerable for long-term administration to individuals in receipt of first-line oxaliplatin-based chemotherapy for inoperable colorectal cancer. Secondary outcome measures will include observation of any changes in neuropathic side-effects of chemotherapy, improvement to progression-free or overall survival and identification of putative efficacy biomarkers in plasma. The results will be disseminated via presentation at national and international conferences, via publication in appropriate peer-reviewed journals and via the Cancer Research UK/Department of Health Experimental Cancer Medicine Centre Network. This trial has full ethical and institutional approval, and commenced recruitment in February 2012.. ClinicalTrials.gov ( NCT01490996 , registered 7(th) December 2011), European Drug Regulating Authorities (EudraCT 2011-002289-19, registered 13(th) May 2011), UKCRN ID#10672.

Topics: Administration, Oral; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Clinical Protocols; Colorectal Neoplasms; Curcumin; Disease Progression; Disease-Free Survival; Drug Administration Schedule; England; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Organoplatinum Compounds; Oxaliplatin; Research Design; Time Factors; Treatment Outcome

In vitro and pre-clinical studies have suggested that addition of the diet-derived agent curcumin may provide a suitable adjunct to enhance efficacy of chemotherapy in models of colorectal cancer. However, the majority of evidence for this currently derives from established cell lines. Here, we utilised patient-derived colorectal liver metastases (CRLM) to assess whether curcumin may provide added benefit over 5-fluorouracil (5-FU) and oxaliplatin (FOLFOX) in cancer stem cell (CSC) models. Combination of curcumin with FOLFOX chemotherapy was then assessed clinically in a phase I dose escalation study. Curcumin alone and in combination significantly reduced spheroid number in CRLM CSC models, and decreased the number of cells with high aldehyde dehydrogenase activity (ALDH(high)/CD133(-)). Addition of curcumin to oxaliplatin/5-FU enhanced anti-proliferative and pro-apoptotic effects in a proportion of patient-derived explants, whilst reducing expression of stem cell-associated markers ALDH and CD133. The phase I dose escalation study revealed curcumin to be a safe and tolerable adjunct to FOLFOX chemotherapy in patients with CRLM (n = 12) at doses up to 2 grams daily. Curcumin may provide added benefit in subsets of patients when administered with FOLFOX, and is a well-tolerated chemotherapy adjunct.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Colorectal Neoplasms; Curcumin; Dose-Response Relationship, Drug; Fluorouracil; Heterografts; Humans; Leucovorin; Liver Neoplasms; Mice; Mice, Inbred NOD; Mice, SCID; Neoplastic Stem Cells; Organoplatinum Compounds; Oxaliplatin; Spheroids, Cellular

Curcumin, the main constituent of turmeric, is suspected to possess cancer chemopreventive properties. Pharmacokinetic and pharmacodynamic parameters have been reported, but few data exist describing whether methodologies are suitably robust for curcuminoid detection in colonic biopsy specimens. Information on the acceptability of prolonged administration of daily curcumin is not available. This is of vital importance to implement chemoprevention strategies. This study aimed to quantify levels of curcuminoids in colorectal mucosa of patients undergoing colorectal endoscopy or surgical resection and to obtain information on the acceptability and compliance with daily curcumin. Curcumin C3 complex (2.35 g) was administered to patients once daily for 14 days before endoscopic biopsy or colonic resection. Safety and tolerance were monitored. Analysis of curcuminoids in plasma, urine, and colonic mucosa was conducted by ultraperformance liquid chromatography (UPLC)-UV with characterization by liquid chromatography/tandem mass spectrometry (LC/MS-MS). Twenty-four of 26 patients commencing curcumin completed the course. Six patients reported mild gastrointestinal adverse events. Curcuminoids were detectable in nine of 24 plasma samples, 24 of 24 urine samples, and in the colonic mucosa of all 23 biopsied participants. Mean tissue levels were 48.4 μg/g (127.8 nmol/g) of parent curcuminoids. The major conjugate, curcumin glucuronide, was detectable in 29 of 35 biopsies. High levels of topical curcumin persisted in the mucosa for up to 40 hours postadministration. Sixteen participants (67%) stated that they would take curcumin long-term should it be of proven benefit. In summary, pharmacologically active levels of curcumin were recovered from colonic mucosa. The regimen used here seems safe, and patients support its use in long-term trials.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Phytogenic; Biological Availability; Carcinoma; Colon; Colorectal Neoplasms; Curcumin; Female; Humans; Intestinal Mucosa; Male; Middle Aged; Patient Acceptance of Health Care; Patient Compliance; Pilot Projects; Time Factors

Biological therapies can be beneficial in cancer patients. The present study aims to examine the inhibitory mechanism of curcumin on cancer cells in patients with colorectal cancer. The results showed that curcumin administration increased body weight, decreased serum TNF-alpha levels, increased apoptotic tumor cells, enhanced expression of p53 molecule in tumor tissue, and modulated tumor cell apoptotic pathway. We conclude that the curcumin treatment improves the general health of patients with colorectal cancer via the mechanism of increased p53 molecule expression in tumor cells and consequently speeds up tumor cell apoptosis.

Topics: Antineoplastic Agents; Apoptosis; Body Weight; Cachexia; Colorectal Neoplasms; Combined Modality Therapy; Curcumin; Digestive System Surgical Procedures; Double-Blind Method; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunohistochemistry; In Situ Nick-End Labeling; Male; Neoplasm Staging; Radiotherapy; Tumor Necrosis Factor-alpha; Tumor Suppressor Protein p53; Up-Regulation

Curcumin is derived from the spice tumeric and has antiinflammatory and antineoplastic effects in vitro and in animal models, including preventing aberrant crypt foci (ACF) and adenomas in murine models of colorectal carcinogenesis. Inhibiting the production of the procarcinogenic eicosanoids prostaglandin E₂ (PGE₂) and 5-hydroxyeicosatetraenoic acid (5-HETE) can suppress carcinogenesis in rodents. Curcumin reduces mucosal concentrations of PGE₂ (via inhibition of cyclooxygenases 1 and 2) and 5-HETE (via inhibition of 5-lipoxygenase) in rats. Although preclinical data support curcumin activity in many sites, the poor bioavailability reported for this agent supports its use in the colorectum. We assessed the effects of oral curcumin (2 g or 4 g per day for 30 days) on PGE₂ within ACF (primary endpoint), 5-HETE, ACF number, and proliferation in a nonrandomized, open-label clinical trial in 44 eligible smokers with eight or more ACF on screening colonoscopy. We assessed pre- and posttreatment concentrations of PGE₂ and 5-HETE by liquid chromatography tandem mass spectroscopy in ACF and normal-tissue biopsies; ACF number via rectal endoscopy; proliferation by Ki-67 immunohistochemistry; and curcumin concentrations by high-performance liquid chromatography in serum and rectal mucosal samples. Forty-one subjects completed the study. Neither dose of curcumin reduced PGE₂ or 5-HETE within ACF or normal mucosa or reduced Ki-67 in normal mucosa. A significant 40% reduction in ACF number occurred with the 4-g dose (P < 0.005), whereas ACF were not reduced in the 2-g group. The ACF reduction in the 4-g group was associated with a significant, five-fold increase in posttreatment plasma curcumin/conjugate levels (versus pretreatment; P = 0.009). Curcumin was well tolerated at both 2 g and 4 g. Our data suggest that curcumin can decrease ACF number, and this is potentially mediated by curcumin conjugates delivered systemically.

Topics: Adult; Aged; Anticarcinogenic Agents; Biopsy; Colorectal Neoplasms; Curcumin; Dinoprostone; Endoscopy; Female; Gene Expression Regulation, Neoplastic; Humans; Ki-67 Antigen; Male; Middle Aged; Smoking; Treatment Outcome

Curcumin, a constituent of the spice turmeric, has been shown to reduce the adenoma burden in rodent models of colorectal cancer accompanied by a reduction of levels of the oxidative DNA adduct 3-(2-deoxy-beta-di-erythro-pentafuranosyl)-pyr[1,2-alpha]-purin-10(3H)one (M(1)G) and of expression of the enzyme cyclooxygenase-2 (COX-2). We tested the hypothesis that pharmacologically active levels of curcumin can be achieved in the colorectum of humans as measured by effects on levels of M(1)G and COX-2 protein. Patients with colorectal cancer ingested curcumin capsules (3,600, 1,800, or 450 mg daily) for 7 days. Biopsy samples of normal and malignant colorectal tissue, respectively, were obtained at diagnosis and at 6 to 7 hours after the last dose of curcumin. Blood was taken 1 hour after the last dose of curcumin. Curcumin and its metabolites were detected and quantitated by high-performance liquid chromatography with detection by UV spectrophotometry or mass spectrometry. M(1)G levels and COX-2 protein expression were measured by immunoslot blot and Western blotting, respectively. The concentrations of curcumin in normal and malignant colorectal tissue of patients receiving 3,600 mg of curcumin were 12.7 +/- 5.7 and 7.7 +/- 1.8 nmol/g, respectively. Curcumin sulfate and curcumin glucuronide were identified in the tissue of these patients. Trace levels of curcumin were found in the peripheral circulation. M(1)G levels were 2.5-fold higher in malignant tissue as compared with normal tissue (P < 0.05 by ANOVA). Administration of curcumin (3,600 mg) decreased M(1)G levels from 4.8 +/- 2.9 adducts per 107 nucleotides in malignant colorectal tissue to 2.0 +/- 1.8 adducts per 107 nucleotides (P < 0.05 by ANOVA). COX-2 protein levels in malignant colorectal tissue were not affected by curcumin. The results suggest that a daily dose of 3.6 g curcumin achieves pharmacologically efficacious levels in the colorectum with negligible distribution of curcumin outside the gut.

Topics: Administration, Oral; Aged; Antineoplastic Agents; Biomarkers; Biopsy; Blotting, Western; Chromatography, High Pressure Liquid; Colorectal Neoplasms; Curcumin; Cyclooxygenase 2; DNA Adducts; Female; Humans; Male; Mass Spectrometry; Membrane Proteins; Middle Aged; Prostaglandin-Endoperoxide Synthases

Curcumin, a polyphenolic antioxidant derived from a dietary spice, exhibits anticancer activity in rodents and in humans. Its efficacy appears to be related to induction of glutathione S-transferase enzymes, inhibition of prostaglandin E(2) (PGE(2)) production, or suppression of oxidative DNA adduct (M(1)G) formation. We designed a dose-escalation study to explore the pharmacology of curcumin in humans. Fifteen patients with advanced colorectal cancer refractory to standard chemotherapies consumed capsules compatible with curcumin doses between 0.45 and 3.6 g daily for up to 4 months. Levels of curcumin and its metabolites in plasma, urine, and feces were analyzed by high-pressure liquid chromatography and mass spectrometry. Three biomarkers of the potential activity of curcumin were translated from preclinical models and measured in patient blood leukocytes: glutathione S-transferase activity, levels of M(1)G, and PGE(2) production induced ex vivo. Dose-limiting toxicity was not observed. Curcumin and its glucuronide and sulfate metabolites were detected in plasma in the 10 nmol/L range and in urine. A daily dose of 3.6 g curcumin engendered 62% and 57% decreases in inducible PGE(2) production in blood samples taken 1 hour after dose on days 1 and 29, respectively, of treatment compared with levels observed immediately predose (P < 0.05). A daily oral dose of 3.6 g of curcumin is advocated for Phase II evaluation in the prevention or treatment of cancers outside the gastrointestinal tract. PGE(2) production in blood and target tissue may indicate biological activity. Levels of curcumin and its metabolites in the urine can be used to assess general compliance.

Topics: Administration, Oral; Aged; Antineoplastic Agents; Biomarkers; Colorectal Neoplasms; Curcumin; Dinoprostone; Female; Glutathione Transferase; Humans; Male; Middle Aged; Patient Compliance

Curcuma spp. extracts, particularly the dietary polyphenol curcumin, prevent colon cancer in rodents. In view of the sparse information on the pharmacodynamics and pharmacokinetics of curcumin in humans, a dose-escalation pilot study of a novel standardized Curcuma extract in proprietary capsule form was performed at doses between 440 and 2200 mg/day, containing 36-180 mg of curcumin. Fifteen patients with advanced colorectal cancer refractory to standard chemotherapies received Curcuma extract daily for up to 4 months. Activity of glutathione S-transferase and levels of a DNA adduct (M(1)G) formed by malondialdehyde, a product of lipid peroxidation and prostaglandin biosynthesis, were measured in patients' blood cells. Oral Curcuma extract was well tolerated, and dose-limiting toxicity was not observed. Neither curcumin nor its metabolites were detected in blood or urine, but curcumin was recovered from feces. Curcumin sulfate was identified in the feces of one patient. Ingestion of 440 mg of Curcuma extract for 29 days was accompanied by a 59% decrease in lymphocytic glutathione S-transferase activity. At higher dose levels, this effect was not observed. Leukocytic M(1)G levels were constant within each patient and unaffected by treatment. Radiologically stable disease was demonstrated in five patients for 2-4 months of treatment. The results suggest that (a) Curcuma extract can be administered safely to patients at doses of up to 2.2 g daily, equivalent to 180 mg of curcumin; (b) curcumin has low oral bioavailability in humans and may undergo intestinal metabolism; and (c) larger clinical trials of Curcuma extract are merited.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; CA-19-9 Antigen; Carcinoembryonic Antigen; Colorectal Neoplasms; Curcumin; Diarrhea; Dose-Response Relationship, Drug; Female; Glutathione Transferase; Humans; Lymphocytes; Male; Middle Aged; Nausea; Pilot Projects; Plant Extracts; Polymorphism, Genetic; Treatment Outcome

Advancement of cancer prevention and therapy requires clinical development of systemic biomarkers of pharmacological efficacy of the agent under scrutiny. Curcumin, a polyphenol derived from Curcuma spp., has shown wide-ranging chemopreventive activity in preclinical carcinogenic models, in which it inhibits cyclooxygenase (COX)-2 at the transcriptional level. COX-2 has been implicated in the development of many human cancers. To explore the inhibition of COX-2 activity as a systemic biomarker of drug efficacy, a biomarker of potential use in clinical trials of many chemopreventive drugs known to inhibit this enzyme, we measured COX-2 protein induction and prostaglandin E(2) (PGE(2)) production in human blood after incubation with lipopolysaccharide (LPS). When 1 microM curcumin was added in vitro to blood from healthy volunteers, LPS-induced COX-2 protein levels and concomitant PGE(2) production were reduced by 24% and 41%, respectively (P < 0.05 by ANOVA). To test whether effects on COX-2 activity could also be measured after oral dosing in humans, we conducted a dose-escalation pilot study of a standardized formulation of Curcuma extract in 15 patients with advanced colorectal cancer. Basal and LPS-mediated PGE(2) production was measured in blood, twice pretreatment and on days 1, 2, 8, and 29 of treatment. Analysis of basal and LPS-induced PGE(2) production during treatment demonstrated a trend toward dose-dependent inhibition (P < 0.005 by regression analysis), but there was no significant difference compared with values from pretreatment time points. Measurement of leukocyte COX-2 activity should be considered in clinical trials of other agents likely to inhibit this isozyme.

Topics: Administration, Oral; Adult; Antineoplastic Agents; Biomarkers, Tumor; Chemoprevention; Colorectal Neoplasms; Curcuma; Curcumin; Cyclooxygenase 2; Enzyme Induction; Female; Humans; Isoenzymes; Leukocytes; Male; Membrane Proteins; Plant Extracts; Prostaglandin-Endoperoxide Synthases; Regression Analysis; Treatment Outcome

Colorectal cancer (CRC) represents one of the most daunting health problems accompanied by progressive undesirable socio-economic effects. Phytochemicals, bioactive ingredients majorly found in plants, have gained momentum for their potential against CRC occurrence and regression. However, these phytoconstituents are not exempt from biopharmaceutical drawbacks; therefore, novel strategies, especially nanotechnology, are exploited to surmount the aforementioned bottlenecks. The current paper aims to comprehensively review the phytochemical-based nanoformulations and their mechanisms in the setting of CRC.. Electronic databases including Scopus, PubMed, and Web of Science were searched with the keywords "colon cancer" or "colorectal cancer", and "plant", "phytochemical", "extract", or "herb", and "nano", "nanoformulation", "Nanoencapsulation", "nanoparticle", "nanostructure", or "nanoliposome", until January 2021.. Of the 1230 research hits, only 69 articles were consequently analyzed. The results indicated nanoformulations of several secondary plant metabolites such as berberine, camptothecin, colchicine, apigenin, chrysin, fisetin, quercetin, curcumin, gallic acid, resveratrol, and ursolic acid have profound effects in a broad range of preclinical models of CRC. A wide variety of nanoformulations have been utilized to deliver these phytochemicals, such as nanocomposite, nanocolloids, and mesoporous silica nanoparticles, which have consequently decreased tumor angiogenesis and mitochondrial membrane potential, increased radical scavenging activity, induced cell cycle arrest at different phases of the cancer cell cycle, and induction of apoptosis process via decreased anti-apoptotic proteins (BRAF, CD44, and Bcl-2) and increased in pro-apoptotic ones (Bax, Fas, caspase 3,8, and 9), as well as modulated biopharmaceutical properties. Chitosan and PEG and their derivatives are among the polymers exploited in the phytochemicals' nanoformulations.. To conclude, nanoformulated forms of natural ingredients depicted outstanding anti-CRC activity that could hold promise for help in treating CRC. However, well-designed clinical trials are needed to build up a whole picture of the health profits of nanoformulation of natural products in CRC management.

Topics: Colorectal Neoplasms; Curcumin; Humans; Neovascularization, Pathologic; Phytochemicals; Resveratrol

Curcumin is known to suppress the progression of colorectal cancer by inhibiting cancer cell proliferation. In this study, we explored the role of ferroptosis in the antiproliferative properties of curcumin. The effect of curcumin on ferroptosis In Vitro was evaluated in HCT-8 cells. Ferroptosis was first blocked by ferrostatin-1 (Fer-1) and the antiproliferative effect of curcumin was evaluated by determining the levels of ferroptotic markers, including glutathione (GSH), SLC7A11, GPX4, iron, malondialdehyde (MDA), and reactive oxygen species (ROS). An agonist and an inhibitor of PI3K were also used to verify the signaling pathway involved in the antiproliferative effects. Curcumin repressed HCT-8 cell proliferation in a dose-dependent manner. Treating HCT-8 cells with curcumin significantly downregulated GSH, SLC7A11, and GPX4, while significantly increasing levels of iron, MDA, and ROS. In addition, curcumin promoted ferroptosis and reduced proliferation of HCT-8 cells by suppressing the PI3K/Akt/mTOR pathway, and these effects were antagonized by Fer-1. The effects of curcumin were antagonized by a PI3K agonist and reinforced by a PI3K inhibitor. Curcumin triggers ferroptosis and suppresses proliferation of colorectal cancer cells by inhibiting the PI3K/Akt/mTOR signaling pathway. These results indicate its potential as a treatment against colorectal cancer.

Topics: Cell Proliferation; Colorectal Neoplasms; Curcumin; Ferroptosis; Glutathione; Humans; Iron; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Signal Transduction; TOR Serine-Threonine Kinases

Curcumin has a plethora of biological properties, making this compound potentially effective in the treatment of several diseases, including cancer. However, curcumin clinical use is compromised by its poor pharmacokinetics, being crucial to find novel analogs with better pharmacokinetic and pharmacological properties. Here, we aimed to evaluate the stability, bioavailability and pharmacokinetic profiles of monocarbonyl analogs of curcumin. A small library of monocarbonyl analogs of curcumin 1a-q was synthesized. Lipophilicity and stability in physiological conditions were both assessed by HPLC-UV, while two different methods assessed the electrophilic character of each compound monitored by NMR and by UV-spectroscopy. The potential therapeutic effect of the analogs 1a-q was evaluated in human colon carcinoma cells and toxicity in immortalized hepatocytes. Our results showed that the curcumin analog 1e is a promising agent against colorectal cancer, with improved stability and efficacy/safety profile.

Topics: Antineoplastic Agents; Colorectal Neoplasms; Curcumin; Humans

The purpose of this study was using bioinformatics tools to identify biomarkers and molecular factors involved in the diagnosis of colorectal cancer, which are effective for the diagnosis and treatment of the disease.. We determined differentially expressed genes (DEGs) related to colorectal cancer (CRC) using the data series retrieved from GEO database. Then the weighted gene co-expression network analysis (WGCNA) was conducted to explore co-expression modules related to CRC diagnosis. Next, the relationship between the integrated modules with clinical features such as the stage of CRC was evaluated. Other downstream analyses were performed on selected module genes.. In this study, after performing the WGCNA method, a module named blue module which was more significantly associated with the CRC stage was selected for further evaluation. Afterward, the Protein-protein interaction network through sting software for 154 genes of the blue module was constructed and eight hub genes were identified through the evaluation of constructed network with Cytoscape. Among these eight hub genes, upregulation of MMP9, SERPINH1, COL1A2, COL5A2, COL1A1, SPARC, and COL5A1 in CRC was validated in other microarray and TCGA data. Based on the results of the mRNA-miRNA interaction network, SERPINH1 was found as a target gene of miR-940. Finally, results of the DGIDB database indicated that Andecaliximab, Carboxylated glucosamine, Marimastat, Tozuleristide, S-3304, Incyclinide, Curcumin, Prinomastat, Demethylwedelolactone, and Bevacizumab, could be used as a therapeutic agent for targeting the MMP9. Furthermore, Ocriplasmin and Collagenase clostridium histolyticum could target COL1A1, COL1A2, COL5A1, and COL5A2.. Taken together, the results of the current study indicated that seven hub genes including COL1A2, COL5A1, COL5A2, SERPINH1, MMP9, SPARC, and COL1A1 which were upregulated in CRC could be used as a diagnostic and progression biomarker of CRC. On the other hand, miR-940 which targets SERPINH1 could be used as a potential biomarker of CRC. More ever, Andecaliximab, Carboxylated glucosamine, Marimastat, Tozuleristide, S-3304, Incyclinide, Curcumin, Prinomastat, Demethylwedelolactone, Bevacizumab, Ocriplasmin , and Collagenase clostridium histolyticum were introduced as therapeutic agents for CRC which their therapeutic potential should be evaluated experimentally.

Topics: Bevacizumab; Biomarkers; Colorectal Neoplasms; Curcumin; Gene Regulatory Networks; Humans; Matrix Metalloproteinase 9; Microbial Collagenase; MicroRNAs

Topics: Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Curcumin; Humans; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; TOR Serine-Threonine Kinases

Curcumin, a natural phytochemical isolated from tumeric roots, represents a candidate for prevention and therapy of colorectal cancer/CRC. However, the exact mechanism of action and the downstream mediators of curcumin's tumor suppressive effects have remained largely unknown. Here we used a genetic approach to determine the role of the p53/miR-34 pathway as mediator of the effects of curcumin. Three isogenic CRC cell lines rendered deficient for the p53, miR-34a and/or miR-34b/c genes were exposed to curcumin and subjected to cell biological analyses. siRNA-mediated inhibition and ectopic expression of NRF2, as well as Western blot, qPCR and qChIP analyses of its target genes were performed. CRC cells were i.v. injected into NOD/SCID mice and lung-metastases formation was determined by longitudinal, non-invasive imaging. In CRC cells curcumin induced apoptosis and senescence, and suppressed migration and invasion in a p53-independent manner. Curcumin activated the KEAP1/NRF2/ARE pathway by inducing ROS. Notably, curcumin induced miR-34a and miR-34b/c expression in a ROS/NRF2-dependent and p53-independent manner. NRF2 directly induced miR-34a and miR-34b/c via occupying multiple ARE motifs in their promoter regions. Curcumin reverted repression of miR-34a and miR-34b/c induced by IL6 and hypoxia. Deletion of miR-34a and miR-34b/c significantly reduced curcumin-induced apoptosis and senescence, and prevented the inhibition of migration and invasion by curcumin or ectopic NRF2. In CRC cells curcumin induced MET and prevented the formation of lung-metastases in mice in a miR-34a-dependent manner. In addition, we found that curcumin may enhance the therapeutic effects of 5-FU on CRC cells deficient for p53 and miR-34a/b/c. Activation of the KEAP1/NRF2/miR-34a/b/c axis mediates the tumor suppressive activity of curcumin and suggests a new approach for activating miR-34 genes in tumors for therapeutic purposes.

Topics: Animals; Cell Line, Tumor; Colorectal Neoplasms; Curcumin; Gene Expression Regulation, Neoplastic; Kelch-Like ECH-Associated Protein 1; Lung Neoplasms; Mice; Mice, Inbred NOD; Mice, SCID; MicroRNAs; NF-E2-Related Factor 2; Reactive Oxygen Species; Tumor Suppressor Protein p53

Topics: Colorectal Neoplasms; Curcuma; Curcumin; Diarylheptanoids; Humans; Surface-Active Agents; Water

The present study was to investigate the underlying mechanism of the antitumor effect of curcumin in colorectal cancer cells, focusing on the M2 polarization of tumor-associated macrophages (TAMs). The effect of curcumin on the malignant behavior of colorectal cancer cells was investigated by WST assay for cell growth, and Transwell assay for cell migration/invasion. THP-1 cells were differentiated into macrophages and coculture with colorectal cancer cells to study the influence of curcumin on M2 polarization, presenting as the levels of ARG1 mRNA, IL-10, and CD163-positive cells. GEO database was searched for the shared altered gene of curcumin in colorectal cells and human monocytes. Molecular docking was used to visualize the binding between curcumin and MACC1. Curcumin restricted the proliferation, apoptosis, and migration/invasion of HCT 116 and SW620 cells. Curcumin attenuated levels of the M2 macrophage markers, CD163 + cells, IL-10 secretion, and ARG1 mRNA. MACC1 was a target of curcumin in colorectal cancer cells, relating to macrophage. Rescue experiments showed that MACC1 overexpression can reverse the antitumor effect of curcumin in colorectal cancer cells and M2 polarization of TAMs. Curcumin's antiproliferative and anti-migratory effects in colorectal cancer cells may be mediated by MACC1 and inhibition of M2 polarization of TAMs.

Topics: Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Colorectal Neoplasms; Curcumin; Humans; Interleukin-10; Molecular Docking Simulation; RNA, Messenger; Trans-Activators; Tumor Microenvironment; Tumor-Associated Macrophages

Colorectal cancer (CRC) is a major cause of cancer-related deaths in humans, and effective treatments are still needed in clinical practice. Despite significant developments in anticancer drugs and inhibitors, their poor stability, water solubility, and cellular membrane permeability limit their therapeutic efficacy. To address these issues, multifunctional CaCO

Topics: Antineoplastic Agents; Colorectal Neoplasms; Curcumin; Humans; Hyaluronic Acid; Nanoparticles

Colorectal cancer (CRC) is one of the most common cancers worldwide. Many factors such as stress, lifestyle, and dietary habits are known to play a role in the initiation and progression of the disease. Herbal therapeutic agents including curcumin can hold a great potential against cancer treatment; however, their efficacy on CRC is still under investigation. Herein, we evaluated the anticancer mechanism of curcumin on four different CRC cell lines.. Cells were treated with curcumin for 24, 48 and 72 h, and IC50 doses for each cell line were calculated. Mechanistic studies were conducted with the lowest IC50 dose determined for each cell line by evaluating apoptosis and necrosis, cell division, and NLRP3-mediated pyroptosis.. Curcumin treatment significantly decreased viability while increasing the SubG1 phase in all cell lines tested, indicating apoptosis is the main programmed cell death pathway activated upon curcumin treatment in CRC. In terms of pyroptosis, components of NLRP3 inflammasome were found to be elevated in SW480 and HCT116 cell lines, although to a lesser extent in the latter, and NLRP3 inflammasome activation was not observed in LoVo and HT29 cells.. Our results reveal that while curcumin effectively induces apoptosis, its effects on NLRP3-inflammasome mediated pyroptosis vary. Our results underline the need for further research focusing on the other inflammasome complexes to confirm the differential effects of curcumin on CRC.

Topics: Apoptosis; Colorectal Neoplasms; Curcumin; Humans; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Pyroptosis

Colorectal cancer (CRC) is a common malignancy that can significantly diminish patients' quality of life. Astragalus mongholicus Bunge-Curcuma aromatica Salisb. (AC) is an ancient Chinese medicinal combination used for the treatment of CRC. However, the core ingredients and targets involved in regulating lipid and amino acid metabolism in CRC remain unknown. We aimed to explore the key components and pharmacological mechanisms of AC in the treatment of CRC through a comprehensive analysis of network metabolomics, network pharmacology, molecular docking, and biological methods.. Ultra-performance liquid chromatography/mass spectrometry (MS) was used for quality control. Gas chromatography/MS and liquid chromatography/MS were used to detect metabolites in the feces and serum of CRC mice. A network pharmacology approach and molecular docking were used to explore the potential genes involved in the CRC-target-component network. The effect of AC on tumor immunity was investigated using flow cytometry and polymerase chain reaction.. AC, high-dose AC, and 5-fluorouracil treatment reduced liver metastasis and tumor mass. Compared with the CRC group, 2 amino acid metabolites and 14 lipid metabolites (LPC, PC, PE) were upregulated and 15 amino acid metabolites and 9 lipid metabolites (TG, PE, PG, 12-HETE) were downregulated. Subsequently, through network analysis, four components and six hub genes were identified for molecular docking. AC can bind to ALDH1B1, ALDH2, CAT, GOT2, NOS3, and ASS1 through beta-Elemene, canavanine, betaine, and chrysanthemaxanthin. AC promoted the responses of M1 macrophages and down-regulated the responses of M2 macrophages, Treg cells, and the gene expression of related factors.. Our research showed that AC effectively inhibited the growth and metastasis of tumors and regulated metabolism and immunity in a CRC mouse model. Thus, AC may be an effective alternative treatment option for CRC.

Topics: Amino Acids; Animals; Astragalus propinquus; Colorectal Neoplasms; Curcuma; Drugs, Chinese Herbal; Lipids; Metabolomics; Mice; Molecular Docking Simulation; Quality of Life

This chapter presents a protocol for studying the effects of curcumin in a colorectal cell line and a mouse model of colitis-associated colon carcinogenesis. The protocol using the CT26 cell line incorporates cell proliferation, migration, invasion, spheroid formation, cell cycle, polymerase chain reaction (PCR), and western blot analyses. For the mouse model, this involved a macroscopic and histological examination of the colon and assays for oxidative damage markers.

Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Movement; Cell Proliferation; Colorectal Neoplasms; Curcumin; Mice

Colorectal cancer (CRC) is one of the most lethal and prevalent malignancies world-wide. Currently, surgery, radiotherapy and chemotherapy are clinically applied as common approaches for CRC patients. Cisplatin is one of the most frequently used chemotherapy drugs for diverse cancers. Although chemotherapeutic strategies have improved the prognosis and survival of cancer patients, development of cisplatin resistance has led to cancer recurrence. Curcumin, isolated from turmeric, has been used as an effective anti-cancer agent. However, the molecular mechanisms for curcumin-mediated cisplatin sensitivity of CRC have not been elucidated. This study aimed to investigate the effects of curcumin treatment on cisplatin-resistant CRC cells.. Expression levels of miRNAs and mRNAs were determined by qRT-PCR. Protein expression levels were detected by Western blotting. Cell responses to curcumin treatments were evaluated by MTT assay, Clonogenic assay and Annexin V apoptosis assay. The glutamine metabolism of colon cancer cells was assessed by glutamine uptake and glutaminase (GLS) activity. The binding of miR-137 on 3' UTR of GLS was validated by Western blotting and luciferase assay.. Results demonstrated that curcumin significantly synergized with cisplatin (combination index <1) to suppress proliferation of colon cancer cells compared with curcumin or cisplatin alone. Moreover, from the established cisplatin-resistant cell line (HT-29), glutamine metabolism was remarkedly elevated in cisplatin-resistant CRC cells that displayed a glutamine addictive phenotype. Furthermore, curcumin treatments attenuated glutamine metabolism in colon cancer cells. Under low glutamine supply, colon cancer cells showed less sensitivity to curcumin. Using a microRNA (miRNA) microArray assay, miR-137, a tumor suppressor in colon cancer, was significantly induced by curcumin treatments in CRC cells. Bioinformatics analysis and a luciferase assay illustrated miR-137 directly targeted the 3' UTR of GLS mRNA. Rescue experiments demonstrated that miR-137-induced cisplatin sensitization was through targeting of GLS. Finally, curcumin treatment overcame cisplatin resistance through miR-137-mediated glutamine inhibition.. Collectively, these results indicate that curcumin could be clinically applied as an anti-chemoresistance approach against CRC by modulating miR-137-inhibited glutamine metabolism.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cisplatin; Colorectal Neoplasms; Curcumin; Glutaminase; Humans; MicroRNAs

Topics: Antineoplastic Agents; Cell Line, Tumor; Colorectal Neoplasms; Curcumin; HCT116 Cells; Humans; Liposomes; Methotrexate; Particle Size

Recent evidences highlight a role of the mitochondria calcium homeostasis in the development of colorectal cancer (CRC). To overcome treatment resistance, we aimed to evaluate the role of the mitochondrial sodium-calcium-lithium exchanger (NCLX) and its targeting in CRC. We also identified curcumin as a new inhibitor of NCLX.. We examined whether curcumin and pharmacological compounds induced the inhibition of NCLX-mediated mitochondrial calcium (mtCa. In vitro, curcumin exerted strong anti-tumoral activity through its action on NCLX with mtCa. Our findings highlight a novel anti-tumoral mechanism of curcumin through its action on NCLX and mitochondria calcium overload that could benefit for therapeutic schedule of patients with MSI CRC.

Topics: Animals; Calcium; Calcium Signaling; Colorectal Neoplasms; Curcumin; Humans; Mice; Microsatellite Instability; Microsatellite Repeats; Mitochondrial Proteins; Sodium-Calcium Exchanger

Organoid is a burgeoning model that have emerged in the past decade. Tumor organoids can simulate specific aspects of the 3D structure, cell type composition and function of real tumors to make up for the deficiencies of cell models and animal models. Curcumin has been found to be effective in suppressing various phases of colorectal cancer development. Nevertheless, there is no clear evidence that the results obtained on cultured cells or animal models can be translated in humans. Therefore, we constructed patient-derived organoids of colorectal cancer to show the curcumin responses of these organoids. Then, a MS-based non-targeted metabolomic strategy was to gain a system-level understanding of the mechanism of curcumin on colorectal cancer patient-derived organoids. Then non-targeted metabonomic analysis found that curcumin mainly regulated the phenylalanine, tyrosine and tryptophan biosynthesis, nicotinate and nicotinamide metabolism, purine metabolism in the organoids of colorectal cancer. Our research provided a reference for further revealing the role of curcumin in human-derived colorectal cancer-like solid tumors.

Topics: Animals; Cells, Cultured; Colorectal Neoplasms; Curcumin; Humans; Organoids

Herein, redox responsive chitosan/stearic acid nanoparticles (CSSA NPs) (≈200 nm) are developed for dual drug delivery. These degradable nanoparticles are prepared based on disulfide (SS) crosslinking chemistry avoiding the use of any external crosslinking agent. CSSA NPs are further loaded with both DOX (hydrophilic) and curcumin (hydrophobic) drugs with ≈86 % and ≈82 % encapsulation efficiency respectively. This approach of combining anticancer therapeutics having different mode of anticancer action allows to develop systems for cancer therapy with enhanced efficacy. In vitro drug release experiments clearly exhibit the low leakage of drug under physiological conditions while ≈98 % DOX and ≈96 % curcumin is released after 136 h under GSH reducing conditions. The cytotoxicity experiments against HCT116 cells demonstrate higher cytotoxicity of dual drug loaded CSSA NPs. In vivo biodistribution experiments with c57bl/6j mice confirms the retention of CSSA NPs in the colon area up to 24 h exhibiting their potential for colorectal cancer therapy.

Topics: Animals; Chitosan; Colorectal Neoplasms; Curcumin; Disulfides; Doxorubicin; Drug Carriers; Drug Delivery Systems; Drug Liberation; Mice; Nanoparticles; Stearic Acids; Tissue Distribution

Curcumin, a polyphenol compound derived from the Curcuma longa L, and crocin, a hydrophilic carotenoid from Crocus Sativus Linnaeus, are traditionally used in food preparations in many countries and could act as chemopreventive compounds against several diseases, including cancer. In this study, the synergistic effect of curcumin and crocin was investigated for the first time on inducing apoptosis and suppressing colorectal cancer cells (SW-480 cell line).. MTT, Annexin V-FITC/PI, and DAPI staining tests were employed to evaluate cell viability and apoptosis induction, respectively. The combined effect of curcumin and crocin on the expression of genes involved in apoptosis and proliferation was quantified using real-time PCR. The combination therapy effect on cell cycle progression was also evaluated by flow cytometry. Based on the obtained results, curcumin and crocin treatment could cooperatively reduce cell viability and induce apoptosis in SW-480 cells by modulating the expression of Bax, Bcl-2, Caspase-3, Caspase-8, Caspase-9, Jak2, Stat3, and Akt1 genes. Besides, curcumin and crocin were able to synergistically increase the cell cycle arrest at the sub G1 phase, induce autophagy and decrease the clonogenic ability of SW-480 cells.. These results suggested that curcumin and crocin combination could be considered a more effective therapeutic strategy for inhibiting colorectal cancer.

Topics: Apoptosis; Carotenoids; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Curcumin; Humans

Curcumin has been testified to repress the development of multiple tumor cells. Nevertheless, the function of curcumin in colorectal cancer (CRC) is not completely clarified. This research was to explore the influence of curcumin on the development of CRC cells and its mechanism. An examination of circular RNA (circ) HN1, microRNA (miR)-302a-3p and phosphoinositide-3-kinase regulatory subunit 3 (PIK3R3) levels in clinical tissues was performed. Assessments of cell development including proliferation, apoptosis, migration, invasion, as well as epithelial-mesenchymal transition were conducted. The effects of curcumin and circHN1 were verified by in vivo tumor implantation experiments. The interaction of miR-302a-3p with circHN1 or PIK3R3 was analyzed. Curcumin repressed CRC cell development in a concentration-dependent manner. CircHN1 expression was augmented in CRC. Augmentation of circHN1 was able to turn around the repressive effects of curcumin on CRC cells. In vivo experiments indicated that low expression of circHN1 further promoted curcumin-mediated inhibition of CRC tumor growth. MiR-302a-3p was a target of circHN1, and suppression of miR-302a-3p was able to turn around the treatment effect of curcumin on CRC cells. Additionally, PIK3R3 was targeted by miR-302a-3p, and curcumin modulated the malignancy of CRC cells through the circHN1/miR-302a-3p/PIK3R3 pathway.

Topics: Cell Cycle Proteins; Cell Line, Tumor; Cell Movement; Cell Proliferation; Colorectal Neoplasms; Curcumin; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Humans; MicroRNAs; Microtubule-Associated Proteins; Phosphatidylinositol 3-Kinases; RNA, Circular

Curcumin (CUR), a curcuminoid originating from turmeric root, possesses diverse pharmacological applications, including potent anticancer properties. However, the use of this efficacious agent in cancer therapy has been limited due to low water solubility and poor bioavailability. To overcome these problems, a drug delivery system was established as an excipient allowing improved dispersion in aqueous media coupled with enhanced in vitro anticancer effects. Different analyses such as UV-vis spectroscopy, differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), solubility and dissolution assays were determined to monitor the successful encapsulation of CUR within the inner cavity of a β-cyclodextrin (β-CD) complex. The results indicated that water solubility was improved by 205.75-fold compared to pure CUR. Based on cytotoxicity data obtained from MTT assays, the inclusion complex exhibited a greater decrease in cancer cell viability compared to pure CUR. Moreover, cancer cell migration rates were decreased by 75.5% and 38.92%, invasion rates were decreased by 37.7% and 35.7%, while apoptosis rates were increased by 26.3% and 14.2%, and both caused caspase 3 activation toward colorectal cancer cells (SW480 and HCT116 cells). This efficacious formulation that enables improved aqueous dispersion is potentially useful and can be extended for various chemotherapeutic applications. Preliminary toxicity evaluation also indicated that its composition can be safely used in humans for cancer therapy.

Topics: beta-Cyclodextrins; Calorimetry, Differential Scanning; Colorectal Neoplasms; Curcumin; Humans; Solubility; Spectroscopy, Fourier Transform Infrared; Water; X-Ray Diffraction

Herein, we report redox responsive, colon cancer targeting poly(allylamine) (PA)/eudragit S-100 (EU) nanoparticles (PAEU NPs) (≈59 nm). These disulfide crosslinked PAEU NPs are developed via air oxidation of thiolated PA and thiolated EU, eliminating the need of any external crosslinking agent for dual drug delivery. PAEU NPs can effectively encapsulate both hydrophilic doxorubicin (DOX) and hydrophobic curcumin (Cur) drug with ≈85 % and ≈97 % encapsulation efficiency respectively. Here, the combination of drugs having different anticancer mechanism offers the possibility of developing nanosystem with enhanced anticancer efficacy. The developed PAEU NPs show good colloidal stability and low drug release under physiological conditions, while high DOX (≈98 %) and Cur (≈93 %) release is observed in reducing environment (10 mM GSH). Further, DOX and Cur loaded PAEU NPs exhibit higher cancer cell killing efficiency as compared to individual free drugs. In vivo biodistribution studies with Balb/C mice display the retention of PAEU NPs in the colon region up to 24 h presenting the developed approach as an efficient way for colorectal cancer therapy.

Topics: Allylamine; Animals; Colorectal Neoplasms; Curcumin; Doxorubicin; Mice; Nanoparticles; Oxidation-Reduction; Tissue Distribution

Metastasis is the main reason for the high mortality rate of colorectal cancer (CRC) patients. Despite the whole improvement in the field of cancer medicine, the treatment options for the patient in the late stages are very restricted. Our previous studies have elucidated metastasis-associated in colon cancer 1 (MACC1) as a direct link to metastasis formation. Therefore, we have aimed to inhibit its expression by using natural products, which are recently the center of most studies due to their low side effects and good tolerability. In this study, we have investigated the effect of one of the promising natural products, curcumin, on MACC1 expression and MACC1-induced tumor-promoting pathways. Curcumin reduced the MACC1 expression, restricted the MACC1-induced proliferation, and was able to reduce the MACC1-induced cell motility as one of the crucial steps for the distant dissemination of the tumor. We further showed the MACC1-dependent effect of curcumin on clonogenicity and wound healing. This study is, to our knowledge, the first identification of the effect of curcumin on the restriction of cancer motility, proliferation, and colony-forming ability by using MACC1 as a target.

Topics: Biological Products; Colorectal Neoplasms; Curcumin; Humans; Trans-Activators; Transcription Factors

Curcumin, a polyphenol derived from turmeric, has multiple biological functions, such as anti-inflammatory, antioxidant, antibacterial and, above all, antitumor activity. Colorectal cancer is a common malignancy of the gastrointestinal tract with an extremely high mortality rate. However, the low bioavailability and poor targeting properties of curcumin generally limit its clinical application. In the present study, we designed a fusion protein GE11-HGFI as a nanodrug delivery system. The protein was connected by flexible linkers, inheriting the self-assembly properties of hydrophobin HGFI and the targeting ability of GE11. The data show that the encapsulation of curcumin by fusion protein GE11-HGFI can form uniform and stable nanoparticles with a size of only 80 nm. In addition, the nanocarrier had high encapsulation efficiency for curcumin and made it to release sustainably. Notably, the drug-loaded nanosystem selectively targeted colorectal cancer cells with high epidermal growth factor receptor expression, resulting in high aggregated concentrations of curcumin at tumor sites, thus showing a significant anticancer effect. These results suggest that the nanocarrier fusion protein has the potential to be a novel strategy for enhancing molecular bioactivity and drug targeting in cancer therapy.

Topics: Antineoplastic Agents; Colorectal Neoplasms; Curcumin; Drug Carriers; Drug Delivery Systems; ErbB Receptors; Humans; Nanoparticles

Colorectal cancer (CRC) is regarded as one of the commonest cancer types around the world. Due to the poor understanding on the causes of CRC formation and progression, this study sets out to investigate the physiological mechanisms by which Astragalus mongholicus Bunge-Curcuma aromatica Salisb. (ARCR) regulates CRC growth and metastasis, and the role in which M2 macrophage polarization plays in this process. An orthotopic-transplant model of CRC was established to evaluate the influence of ARCR on the polarization of M2 macrophage and the growth and metastasis of tumors. Next, the binding affinity among Sp1, ZFAS1, miR-153-5p, and CCR5 was identified using multiple assays. Finally, after co-culture of bone marrow-derived macrophages (BMDM) with CRC cell line CT26.WT, the cell proliferative, invasive, and migrated abilities were assessed in gain- or loss-of-function experiments. ARCR inhibited the infiltration of M2 macrophages into tumor microenvironment to suppress the CRC growth and metastasis in vivo. Additionally, ARCR inhibited the transcription of ZFAS1 by reducing Sp1 expression to repress M2 macrophage polarization. Moreover, ZFAS1 competitively binds to miR-153-3p to upregulate the CCR5 expression. Finally, ARCR suppressed the polarization of M2 macrophages to inhibit the tumor growth and tumor metastasis in CRC by mediating the Sp1/ZFAS1/miR-153-3p/CCR5 regulatory axis. Collectively, ARCR appears to suppress the CRC cell growth and metastasis by suppressing M2 macrophage polarization via Sp1/ZFAS1/miR-153-3p/CCR5 regulatory axis. 1. ARCR suppress the CRC cell growth and metastasis 2. ZFAS1 promotes CCR5 expression by competitively binding to miR-153-3p. 3. Sp1 promotes M2 macrophage polarization by activating ZFAS1 via miR-153-3p/CCR5. 4. The study unveiled a protective target against CRC.

Topics: Astragalus propinquus; Cell Line, Tumor; Cell Movement; Cell Proliferation; Colorectal Neoplasms; Curcuma; Humans; Macrophage Activation; Macrophages; MicroRNAs; Neoplasm Invasiveness; Plant Preparations; Receptors, CCR5; RNA, Long Noncoding; Sp1 Transcription Factor; Tumor Microenvironment

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Cell Line, Tumor; Colorectal Neoplasms; Curcumin; Cytidine Deaminase; Decitabine; Deoxycytidine Kinase; DNA Methylation; Drug Resistance, Neoplasm; Drug Synergism; Humans

Topics: Animals; Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Curcumin; Down-Regulation; Drug Synergism; Fluorouracil; Humans; Inhibitory Concentration 50; Male; Mice, Inbred BALB C; Mice, Nude; Nicotinamide N-Methyltransferase; Phosphorylation; Reactive Oxygen Species; STAT3 Transcription Factor; Xenograft Model Antitumor Assays

Obesity increases the colorectal cancer risk, in part by elevating colonic proinflammatory cytokines. Curcumin (CUR) and supplemental vitamin B-6 each suppress colonic inflammation.. We examined whether the combination of CUR and vitamin B-6 amplifies each supplement's effects and thereby suppress obesity-promoted tumorigenesis.. Male Friend Virus B (FVB) mice (4-week-old; n = 110) received 6 weekly injections of azoxymethane beginning 1 week after arrival. Thereafter, they were randomized to receive a low-fat diet (10% energy from fat), a high-fat diet (HFD; 60% energy from fat), a HFD containing 0.2% CUR, a HFD containing supplemental vitamin B-6 (24 mg pyridoxine HCl/kg), or a HFD containing both CUR and supplemental vitamin B-6 (C + B) for 15 weeks. Colonic inflammation, assessed by fecal calprotectin, and tumor metrics were the primary endpoints. The anti-inflammatory efficacy of the combination was also determined in human colonic organoids.. HFD-induced obesity produced a 2.6-fold increase in plasma IL-6 (P < 0.02), a 1.9-fold increase in fecal calprotectin (P < 0.05), and a 2.2-fold increase in tumor multiplicity (P < 0.05). Compared to the HFD group, the C + B combination, but not the individual agents, decreased fecal calprotectin (66%; P < 0.01) and reduced tumor multiplicity and the total tumor burden by 60%-80% (P < 0.03) in an additive fashion. The combination of C + B also significantly downregulated colonic phosphatidylinositol-4,5-bisphosphate 3-kinase, Wnt, and NF-κB signaling by 31%-47% (P < 0.05), effects largely absent with the single agents. Observations that may explain how the 2 agents work additively include a 2.8-fold increased colonic concentration of 3-hydroxyanthranillic acid (P < 0.05) and a 1.3-fold higher colonic concentration of the active coenzymatic form of vitamin B-6 (P < 0.05). In human colonic organoids, micromolar concentrations of CUR, vitamin B-6, and their combination suppressed secreted proinflammatory cytokines by 41%-93% (P < 0.03), demonstrating relevance to humans.. In this mouse model, C + B is superior to either agent alone in preventing obesity-promoted colorectal carcinogenesis. Augmented suppression of procancerous signaling pathways may be the means by which this augmentation occurs.

Topics: Animals; Carcinogenesis; Colorectal Neoplasms; Curcumin; Diet, High-Fat; Dietary Supplements; Male; Mice; Mice, Inbred C57BL; Obesity; Pyridoxine; Vitamin B 6; Vitamins

This study aimed to characterize the hydrogel micro- and macro-particles designed to deliver curcumin to human colon cancer cells (LoVo). Six series of vehicles based on sodium alginate (micro- and macro-particles, uncoated, coated with chitosan or gelatin) were synthesized. The uncoated microparticles were fabricated using an emulsion-based technique and the uncoated macroparticles with an extrusion technique, with both coupled with ionotropic gelation. The surface morphology of the particles was examined with scanning electron microscopy and the average size was measured. The encapsulation efficiency, moisture content, and swelling index were calculated. The release of curcumin from the particles was studied in an experiment simulating the conditions of the stomach, intestine, and colon. To evaluate the anticancer properties of such targeted drug delivery systems, the cytotoxicity of both curcumin-loaded and unloaded carriers to human colon cancer cells was assessed. The microparticles encapsulated much less of the payload than the macroparticles and released their content in a more prolonged manner. The unloaded carriers were not cytotoxic to LoVo cells, while the curcumin-loaded vehicles impaired their viability-more significantly after incubation with microparticles compared to macroparticles. Gelatin-coated or uncoated microparticles were the most promising carriers but their potential anticancer activity requires further thorough investigation.

Topics: Adenocarcinoma; Alginates; Antineoplastic Agents; Cell Line, Tumor; Chitosan; Colorectal Neoplasms; Curcumin; Drug Carriers; Drug Delivery Systems; Gelatin; Humans; Hydrogels; Microspheres; Particle Size

Adenomatous polyps are precancerous lesions associated with a higher risk of colorectal cancer (CRC). Curcumin and anthocyanins have shown promising CRC-preventive activity in preclinical and epidemiological studies. The objective of this window-of-opportunity, proof-of principle trial was to evaluate the effect of curcumin combined with anthocyanin supplements on tissue biomarkers of colorectal adenomatous polyps. Eligible patients received either anthocyanin and curcumin supplementation or related matching placebo for 4-6 weeks before polyp removal. Adenomatous polyps and adjacent tissue biopsies were collected at baseline and after supplementation for immunohistochemical assessment of β-catenin, NF-kappa B (NF-κB), Ki-67, P53, and dysplasia. No differences were observed in baseline biomarker expression between normal and dysplastic tissues. The combination of anthocyanins and curcumin resulted in a significant borderline reduction of NF-κB immunohistochemistry (IHC) expression in adenoma tissue (geometric mean ratio (GMR): 0.72; 95% confidence interval (CI): 0.51-1.00;

Topics: Adenomatous Polyps; Aged; Aged, 80 and over; Anthocyanins; Colorectal Neoplasms; Curcumin; Dietary Supplements; Female; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Ki-67 Antigen; Male; Middle Aged; NF-kappa B; Tumor Suppressor Protein p53

The development of cisplatin resistance is a common cause of cancer recurrence in colorectal cancer (CRC). Though many studies have reported the oncogenic function of long non-coding RNA (LncRNA) KCNQ1OT1 in multiple cancers, few studies explored its role in cisplatin resistance of CRC. Curcumin is a natural phenolic compound extracted from turmeric, which can effectively suppress cisplatin resistance in CRC. This study aims to expound the role of KCNQ1OT1 in cisplatin resistance in CRC cells and whether KCNQ1OT1 participates in the reversal effect of curcumin on cisplatin resistance in CRC. The interplay between KCNQ1OT1 and miR-497 was determined using RNA pull-down assay and dual-luciferase reporter gene assay. The combination of B-cell lymphoma 2 (Bcl-2) and miR-497 was confirmed using dual-luciferase reporter gene assay. Compared with CRC cell line HCT8, the cisplatin-resistant CRC cell line HCT8/DDP exhibited a higher expression level of KCNQ1OT1. Functionally, the silence of KCNQ1OT1 suppressed proliferation and boosted apoptosis in HCT8/DDP cells. Subsequently, we found that KCNQ1OT1 could act as a sponge of miR-497 and remove the suppressive effect of miR-497 on Bcl-2 expression. Curcumin treatment restrained proliferation and facilitated apoptosis in HCT8/DDP cells. While KCNQ1OT1 overexpression removed the effect of curcumin on HCT8/DDP cells via miR-497/ Bcl-2 axis. Finally, the in vivo experiments showed that the inhibitory effect of curcumin on the growth of cisplatin-resistant CRC cells was reserved by the ectopic expression of KCNQ1OT1. In conclusion, KCNQ1OT1 aggravated cisplatin resistance in CRC cells via the miR-497/Bcl-2 axis. Administration of curcumin could effectively downregulate KCNQ1OT1 expression, thus reversing cisplatin resistance in CRC cells.

Topics: Cell Line, Tumor; Cisplatin; Colorectal Neoplasms; Curcumin; Drug Resistance, Neoplasm; Humans; Potassium Channels, Voltage-Gated; RNA, Neoplasm

Topics: Animals; Antineoplastic Agents; Biological Availability; Cell Death; Cell Line, Tumor; Colorectal Neoplasms; Curcumin; Drug Carriers; Drug Liberation; Humans; Lipids; Male; Milk; Molecular Docking Simulation; Nanoparticles; Pectins; Rats; Rats, Wistar; Zebrafish

Colorectal cancer stem cells (CSCs) have the potential for self-renewal, proliferation, and differentiation. And LGR5 is a stem cell marker gene of colorectal cancer. Curcumin can suppress oncogenicity of many cancer cells, yet the effect and mechanism of curcumin in LGR5(+) colorectal cancer stem cells (CSCs) have not been studied. In this study, we studied the effect of curcumin on LGR5(+) colorectal CSCs using the experiments of tumorsphere formation, cell viability and cell apoptosis. Then autophagy analysis, RNA-Seq, and real-time PCR were used to identify the mechanism responsible for the inhibition of LGR5(+) colorectal CSCs. Our results showed that curcumin inhibited tumorsphere formation, decreased cell viability in a dose-dependent manner, and also promoted apoptosis of LGR5(+) colorectal CSCs. Next, we found curcumin induced autophagy of LGR5(+) colorectal CSCs. When LGR5(+) colorectal CSCs were co-treated with curcumin and the autophagy inhibitor (hydroxychloroquine), curcumin-induced cell proliferation inhibition decreased. In addition, we also found that curcumin inhibited the extracellular matrix (ECM)-receptor interaction pathway via the downregulation of the following genes: GP1BB, COL9A3, COMP, AGRN, ITGB4, LAMA5, COL2A1, ITGB6, ITGA1, and TNC. Further, these genes were transcriptionally regulated by TFAP2A, and the high expression of TFAP2A was associated with poor prognosis in colorectal cancer. In conclusion, curcumin suppressed LGR5(+) colorectal CSCs, potentially by inducing autophagy and repressing the oncogenic TFAP2A-mediated ECM pathway.

Topics: Apoptosis; Autophagy; Cell Line, Tumor; Cell Proliferation; Cell Survival; Colorectal Neoplasms; Curcumin; Extracellular Matrix; Humans; Neoplastic Stem Cells; Receptors, G-Protein-Coupled; Spheroids, Cellular; Transcription Factor AP-2

Colon cancer treatments include surgery, radiotherapy, and chemotherapy. Chemotherapy using 5-fluorouracil (5-FU) has been widely applied to treat colorectal cancer (CRC). However, it is important to explore the use of chemotherapy drugs in combination with other agents to decrease severe adverse effects.. This study aimed to investigate the effects of curcumin in combination with 5-FU on the proliferation, migration, and apoptosis of CRC SW620 cell line both in vitro and in vivo.. Flow cytometry was used to study the effect of curcumin on chemotherapy-induced apoptosis in CRC cells. The mechanism of curcumin's enhanced antitumor effect in vivo was investigated using gene knockdown, TUNEL, western blot, qRT-PCR and immunohistochemistry.. The results showed a synergistic effect of the two compounds on CRC cells. Considerable reduction in the proliferation and migration of SW620 cells was observed in the combination treatment group. Significantly increased apoptosis rate extended the survival of immunodeficient mice in the combination group as compared to that of the 5-FU group (p < 0.05). The results showed that curcumin significantly inhibited pERK signaling and downregulated L1 expression in SW620 cells.. We conclude that curcumin promotes chemosensitivity of CRC cells to 5-FU by downregulating L1 expression. Our findings provide experimental evidence for the synergism between curcumin and 5-FU, which can be utilized in clinical applications for reducing the toxicity and adverse effects of 5-FU.

Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Curcumin; Down-Regulation; Drug Synergism; Female; Fluorouracil; Humans; Leukocyte L1 Antigen Complex; Mice; Mice, Nude; Signal Transduction; Xenograft Model Antitumor Assays

Despite recent advances in therapy, colorectal cancer remains a leading cause of death in affected people. Curcumin is the main bioactive compound of turmeric that has been demonstrated as an effective agent against cancer. However, its poor stability and bioavailability limit therapeutic application. We previously showed that delivery of curcumin by using gemini surfactant nanoparticles called gemini curcumin (Gemini-Cur) could improve its solubility, uptake and toxic effect on breast and ovarian cancer cells. Here, we aimed to investigate the anticancer activity of Gemini-Cur in both p53-mutant and p53-wild type colorectal cancer cells. The toxicity of Gemini-Cur on HT-29 and HCT116 was studied through MTT, uptake kinetics, fluorescence microscopy, annexin V/FITC, and cell cycle assays. Also, real-time PCR and western blotting were performed to evaluate the expression of p53, p21, BAX, BCL-2, and NOXA genes. Our data showed that Gemini-Cur not only enters cells quite rapidly compared to free curcumin crystals, but also suppresses HT-29 and HCT-116 cells proliferation in a time- and dose-dependent manner (p < 0.001). The IC50 values as well as apoptosis assays showed that p53-wild type cells are sensitive to Gemini-Cur. Flow cytometry also revealed that the number of apoptotic cells is dramatically increased in HCT-116 cells earlier than HT-29 cells (p < 0.0001). Gemini-Cur upregulated apoptotic genes including p53 (in both mutant and wild-type forms), p21, NOXA and BAX while decreased anti-apoptotic BCL-2 in mRNA and protein level (p < 0.0001). As a hallmark of apoptosis, the expression ratio of BAX/BCL-2 was significantly increased in all treated cells. Taken together, our findings demonstrated that Gemini-Cur suppresses the proliferation of cancer cells via induction of apoptosis and could be considered as novel nano-formulated phytochemical for cancer targeting.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Colorectal Neoplasms; Curcumin; HCT116 Cells; Humans; Tumor Suppressor Protein p53

We synthesized twelve hybrids based on curcumin and resveratrol, and their structures were elucidated by spectroscopic analysis. The chemopreventive potential of these compounds was evaluated against SW480 human colon adenocarcinoma cells, its metastatic derivative SW620, along with the non-malignant CHO-K1 cell line. Among the tested compounds, hybrids

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; CHO Cells; Colorectal Neoplasms; Cricetinae; Cricetulus; Curcumin; Drug Design; Drug Screening Assays, Antitumor; Fluorouracil; Humans; Resveratrol; Rhodamines

Topics: Adenocarcinoma; Antineoplastic Agents; Apoptosis; Cell Culture Techniques; Cell Line, Tumor; Cell Proliferation; Cell Survival; Colorectal Neoplasms; Curcumin; Drug Screening Assays, Antitumor; Flavanones; Humans; Lab-On-A-Chip Devices; Microfluidic Analytical Techniques; Microfluidics; Neoplasms; Polyphenols; Resveratrol; Tumor Microenvironment

Topics: Antineoplastic Agents; Cell Line, Tumor; Colorectal Neoplasms; Curcumin; Drug Carriers; Drug Delivery Systems; Humans; Nanoparticles; Particle Size

Despite its adverse effects, chemotherapy is generally used for the treatment of colorectal cancer (CRC). Development of supplement preparations targeting cancer stem cells (CSCs) that cause distant metastasis and drug resistance is required. Although curcumin is known to have anti-tumor, hepatoprotective, and hypoglycemic-like actions, its low water solubility, oral absorption, and bioavailability impede its therapeutic uses. Patient-derived organoid cultures can recapitulate heterogeneity, epithelial structures, and molecular imprints of their parental tissues. In the present study, anti-carcinogenic properties of amorphous curcumin (AC), a compound with improved solubility and bioavailability, were evaluated against human CRC organoids. Treatment with AC inhibited the cell viability of CRC organoids in a concentration-dependent manner. AC arrested the cell cycle of CRC organoids and induced apoptosis. AC inhibited phosphorylation of ERK. Expression of downstream signals of ERK, namely c-MYC and cyclin-D1, were inhibited. Expressions of CSC markers, CD44, LGR5, and CD133, were declined in the AC-treated CRC organoids. The combinational treatment of CRC organoids with AC and anti-cancer drugs, oxaliplatin, 5-FU, or irinotecan showed a synergistic activity. In vivo, AC decreased the tumor growth of CRC organoids in mice with the induction of necrotic lesions. In conclusion, AC diminished the cell viability of CRC organoids through the inhibition of proliferation-related signals and CSC marker expression in addition to arresting the cell cycle. Collectively, these data suggest the value of AC as a promising supplement that could be used in combination with anti-cancer drugs to prevent the recurrence and metastasis of CRC.

Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinogenesis; Cell Cycle; Cell Proliferation; Cell Survival; Colorectal Neoplasms; Curcumin; Drug Synergism; Fluorouracil; Humans; Irinotecan; Male; Mice, SCID; Neoplastic Stem Cells; Organoids; Oxaliplatin

We have extended our analyses of (curcumin+sildenafil) biology. The drug combination caused vascularization and degradation of mutant K-RAS that correlated with reduced phosphorylation of ERK1/2, AKT T308, mTORC1, mTORC2, ULK1 S757, STAT3, STAT5, and NFκB and increased phosphorylation of eIF2α, ATM, AMPKα, ULK1 S317; all concomitant with elevated ATG13 S318 phosphorylation and autophagosome formation. Prior studies with drug combinations utilizing sildenafil have delineated an ATM-AMPK-ULK1 S317 pathway and an AKT-mTOR-ULK1 S757 pathway as modules which control ATG S318 phosphorylation and autophagosome formation. The knockdown of PKG reduced cell killing as well as reducing drug-enhanced phosphorylation of ATM, AMPKα, and ATG13. In the absence of PKG, no significant increase in ULK1 S317 phosphorylation was observed. In a Beclin1-dependent fashion, the drug combination reduced the expression of multiple histone deacetylase (HDAC) proteins, including HDAC2 and HDAC3. Molecular knockdown of HDAC2, HDAC3, and especially (HDAC2+HDAC3) significantly reduced the expression of PD-L1 and elevated expression of Class I human major histocompatibility complex. In vivo, (curcumin+sildenafil) enhanced the efficacy of 5-flurouracil against CT26 colorectal tumors. Prior exposure of established CT26 tumors to (curcumin+sildenafil) significantly enhanced the efficacy of a subsequently administered anti-PD-1 antibody. Collectively our data argue that (curcumin+sildenafil) has the potential in several settings to be an efficacious neoadjuvant therapy for colon cancer.

Topics: Animals; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Colorectal Neoplasms; Curcumin; Drug Synergism; Fluorouracil; Histone Deacetylases; Humans; Mice; Mice, Inbred BALB C; Programmed Cell Death 1 Receptor; Sildenafil Citrate; Vasodilator Agents; Xenograft Model Antitumor Assays

Colorectal cancer (CRC) is the second leading cause of cancer death worldwide. Therefore, it is important to establish useful methods for preventing CRC. One prevention strategy involves the use of cancer chemopreventive agents, including functional foods. We focused on the well-known cancer chemopreventive agent curcumin, which is derived from turmeric. However, curcumin has the disadvantage of being poorly soluble in water due to its high hydrophobicity. To overcome this problem, the formation of submicron particles with surface controlled technology has been applied to curcumin to give it remarkably improved water solubility, and this derived compound is named Theracurmin. To date, the preventive effects of Theracurmin on hereditary intestinal carcinogenesis have not been elucidated. Thus, we used Apc-mutant mice, a model of familial adenomatous polyposis, to evaluate the effects of Theracurmin. First, we showed that treatment with 10-20 µM Theracurmin for 24 hours reduced nuclear factor-κB (NF-κB) transcriptional activity in human colon cancer DLD-1 and HCT116 cells. However, treatment with curcumin mixed in water did not change the NF-κB promoter transcriptional activity. As NF-κB is a regulator of inflammation-related factors, we next investigated the downstream targets of NF-κB: monocyte chemoattractant protein-1 (MCP-1) and interleukin (IL)-6. We found that treatment with 500 ppm Theracurmin for 8 weeks inhibited intestinal polyp development and suppressed MCP-1 and IL-6 mRNA expression levels in the parts of the intestine with polyps. This report provides a proof of concept for the ongoing Theracurmin human trial (J-CAP-C study).

Topics: Adenomatous Polyposis Coli; Adenomatous Polyposis Coli Protein; Animals; Carcinogenesis; Chemokine CCL2; Colorectal Neoplasms; Curcumin; Disease Models, Animal; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humans; Inflammation; Interleukin-6; Intestinal Polyps; Intestines; Mice; NF-kappa B

We prepared FA/Nano-Cur micelles and identified their characteristics. The drug release behavior, pharmacokinetics and in vitro anti-tumor activities of FA/Nano-Cur were studied. Furthermore, the in vivo anti-tumor ability assessment and anti-tumor mechanisms investigation were carried out in murine colorectal cancer model.. The present study demonstrated FA/Nano-Cur micelles might be a promising therapeutic agent in colorectal cancer treatment with distinctive advantages of improved bioavailability, sustained drug release, tumor-targeted delivery and low toxicity.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Biological Availability; Cell Line, Tumor; Colorectal Neoplasms; Curcumin; Delayed-Action Preparations; Drug Carriers; Drug Delivery Systems; Drug Liberation; Female; Folic Acid; Mice, Inbred BALB C; Micelles; Nanostructures; Particle Size; Polyesters; Polyethylene Glycols; Rats

Poly(lactide-co-glycolide) (PLGA) colloidal particles stabilized by complexes of two oppositely charged polysaccharides, chitosan (cationic, CS) and sodium carboxymethylcellulose (anionic, NaCMC), were fabricated. Dichloromethane containing dissolved PLGA was first emulsified in an aqueous phase containing mixtures of CS and NaCMC. Evaporation of dichloromethane from the resulting emulsion led to CS/NaCMC-covered-PLGA particles. CS and NaCMC contents affected the short-term stability of PLGA particles and also their intrinsic characteristics. The particles displayed pH-dependent characteristic. Zeta potential varied from +54 to -50 mV when pH was varied from 3 to 10. CS/NaCMC-covered-PLGA particles showed colloidal stability, over a wider pH range as compared to CS-covered-PLGA particles. Curcumin, a model hydrophobic drug, was encapsulated into the particles up to 10 wt% of PLGA. The CS/NaCMC-covered-PLGA particles loaded with curcumin showed delayed release in mildly acidic conditions and faster release in neutral and basic conditions. Cytotoxicity experiments were carried out with human colorectal carcinoma cells.

Topics: Antineoplastic Agents; Carboxymethylcellulose Sodium; Cell Proliferation; Chitosan; Colorectal Neoplasms; Curcumin; Drug Carriers; Drug Delivery Systems; Drug Screening Assays, Antitumor; HCT116 Cells; Humans; Molecular Structure; Particle Size; Polylactic Acid-Polyglycolic Acid Copolymer; Surface Tension; Tumor Cells, Cultured

We have investigated the involvement of the pre-mRNA processing factor 4B (PRP4) kinase domain in mediating drug resistance. HCT116 cells were treated with curcumin, and apoptosis was assessed based on flow cytometry and the generation of reactive oxygen species (ROS). Cells were then transfected with PRP4 or pre-mRNA-processing-splicing factor 8 (PRP8), and drug resistance was analyzed both

Topics: Actin Cytoskeleton; Animals; Apoptosis; Cadherins; Catalytic Domain; Colorectal Neoplasms; Curcumin; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; HCT116 Cells; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Oxidative Stress; Protein Serine-Threonine Kinases; Reactive Oxygen Species; Real-Time Polymerase Chain Reaction; Ribonucleoprotein, U4-U6 Small Nuclear; RNA-Binding Proteins; Up-Regulation; Xenograft Model Antitumor Assays

Modulated electro-hyperthermia (mEHT) is a form of hyperthermia used in cancer treatment. mEHT has demonstrated the ability to activate host immunity by inducing the release of heat shock proteins, triggering apoptosis, and destroying the integrity of cell membranes to enhance cellular uptake of chemo-drugs in tumor cells. Both curcumin and resveratrol are phytochemicals that function as effective antioxidants, immune activators, and potential inhibitors of tumor development. However, poor bioavailability is a major obstacle for use in clinical cancer treatment.. This purpose of this study was to investigate whether mEHT can increase anti-cancer efficacy of nanosized curcumin and resveratrol in in vitro and in vivo models. The in vitro study included cell proliferation assay, cell cycle, and apoptosis analysis. Serum concentration was analyzed for the absorption of curcumin and resveratrol in SD rat model. The in vivo CT26/BALB/c animal tumor model was used for validating the safety, tumor growth curve, and immune cell infiltration within tumor tissues after combined mEHT/curcumin/resveratrol treatment.. The results indicate co-treatment of mEHT with nano-curcumin and resveratrol significantly induced cell cycle arrest and apoptosis of CT26 cells. The serum concentrations of curcumin and resveratrol were significantly elevated when mEHT was applied. The combination also inhibited the growth of CT26 colon cancer by inducing apoptosis and HSP70 expression of tumor cells while recruiting CD3+ T-cells and F4/80+ macrophages.. The results of this study have suggested that this natural, non-toxic compound can be an effective anti-tumor strategy for clinical cancer therapy. mEHT can enable cellular uptake of potential anti-tumor materials and create a favorable tumor microenvironment for an immunological chain reaction that improves the success of combined treatments of curcumin and resveratrol.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Biological Availability; Cell Cycle Checkpoints; Cell Line, Tumor; Colorectal Neoplasms; Combined Modality Therapy; Curcumin; Disease Models, Animal; Drug Screening Assays, Antitumor; Electric Stimulation Therapy; Female; Humans; Hyperthermia, Induced; Macrophages; Male; Mice; Nanoparticles; Rats; Resveratrol; T-Lymphocytes; Tumor Microenvironment

Cathepsins are lysosomal acid hydrolases that make crucial contributions to tumor progression through a variety of signaling mechanisms, including autophagy, cell survival, chemotherapeutic resistance, and metastasis. Herein, we report that cathepsin C (CTSC) silencing upregulates the anticancer potential of curcumin in colorectal cancer cells (CRCs) both in vitro and in athymic mice xenografts. Curcumin treatment enhances CTSC level in CRCs; however, CTSC silencing with subsequent curcumin treatment (sequential treatment) induces ER stress and autophagic dysregulation accompanied by lysosomal permeabilization and ROS generation. This lysosomal permeabilization triggered the cytosolic CTSB mediated BID-dependent mitochondrial membrane permeabilization and thereby caspase-dependent apoptosis. This phenotype can be rescued by CTSB inhibition and NAC, which further supported the involvement of ROS and CTSB in apoptosis following sequential treatment. Indeed, the sequential CTSC silencing and curcumin treatment also significantly curtailed tumor volume as well as ameliorated cytosolic cyt c and tBID protein levels in tumor tissues compared to those in control and individual treatments of CTSC targeting and on curcumin treatment in nude mice xenografts. The results reveal that CTSC can controls the curcumin-induced cytotoxic insult through autophagy maintenance both in vitro and in athymic mice xenografts, thereby providing an insight into the role of CTSC in chemoprevention of CRCs.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Autophagy; Cathepsin C; Colorectal Neoplasms; Curcumin; Endoplasmic Reticulum Stress; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humans; Lysosomes; Mice, Inbred BALB C; Mice, Nude; RNA Interference; Signal Transduction; Xenograft Model Antitumor Assays

BACKGROUND Curcumin is a component of Curcuma longa with various biological activities. The present study aimed to investigate curcumin's inhibitory effects on epithelial-mesenchymal transition (EMT) in colorectal cancer (CRC) cells and possible mechanisms of action underlying these effects. MATERIAL AND METHODS Human SW480 CRC cells were incubated with curcumin at 0.1, 0.2, 0.4, 0.8, or 1.6 μmol/L. The 3-(4,5-Dimethylthiazol-2-Yl)-2,5-Diphenyltetrazolium Bromide (MTT) assay was utilized to evaluate cell viabilities. The DNA methylation levels of the cdx2 promoter were assessed by bisulfite sequencing polymerase chain reaction (BSP). Real-time quantitative PCR was used to measure the mRNA expression levels. Protein expression levels were evaluated with western blotting. Immunofluorescence staining was used to evaluate the nuclear translocation of ß-catenin. RESULTS Curcumin concentrations of 0.1, 0.2, and 0.4 μmol/L showed no significant association with the viability of SW480 cells, which were chosen for subsequent experiments. Curcumin incubation significantly downregulated expression levels of DNA methyltransferase1 (DNMT1), DNMT3a, and the methylation levels of the cdx2 promoter in a concentration-dependent manner. The expression levels of N-cadherin, Vimentin, Wnt3a, Snail1, and Twist, as well as the nuclear translocation levels of ß-catenin, were reduced in a curcumin concentration-dependent manner. The expression levels of E-cadherin were increased in a curcumin concentration-dependent manner. CONCLUSIONS Curcumin negatively regulated transcription factors promoting EMT in CRC cells by decreasing cdx2 promoter DNA methylation and consequently suppressing the CDX2/Wnt3a/ß-catenin signaling pathway.

Topics: Antineoplastic Agents; CDX2 Transcription Factor; Cell Line, Tumor; Colorectal Neoplasms; Curcumin; DNA Methylation; Epithelial-Mesenchymal Transition; Humans; Promoter Regions, Genetic

Curcumin is the main component of the Chinese herbal plant turmeric, which has been demonstrated to possess antitumor and other pharmacological properties. The aim of the present study was to investigate the effects of curcumin on the viability, migration and apoptosis of human colorectal carcinoma HCT‑116 cells, and to explore the underlying molecular mechanisms. In addition, it was investigated whether the antitumor effect of curcumin on HCT‑116 cells could match that of the chemotherapeutic drug 5‑fluorouracil (5‑FU). HCT‑116 cells were treated with curcumin (10, 20 and 30 µM) and 5‑FU (500 µM), and cell viability and proliferation were detected by Cell Counting Kit‑8 and colony formation assays, respectively. The migration and invasion of treated cells were determined using Transwell and carboxyfluorescein succinimidyl amino ester fluorescent labeling assays. Cell cycle distribution and apoptosis rates were detected by flow cytometry. Furthermore, cell morphology changes associated with apoptosis were observed by fluorescence microscopy with acridine orange/ethidium bromide dual staining. To investigate the possible underlying molecular mechanisms, the gene and protein levels of Fas, Fas‑associated via death domain (FADD), caspase‑8, caspase‑3, matrix metalloproteinase (MMP)‑9, nuclear factor (NF)‑κB, E‑cadherin and claudin‑3 were detected using quantitative PCR analysis, zymography and western blotting. The results revealed that curcumin markedly inhibited the viability and proliferation of HCT‑116 cells in a dose‑ and time‑dependent manner. The migration, aggregation and invasion of HCT‑116 cells into the lungs of mice were decreased by curcumin treatment in a dose‑dependent manner. S‑phase arrest and gradually increased apoptotic rates of HCT‑116 cells were observed with increasing curcumin concentrations. Additionally, the mRNA and protein levels of apoptosis‑associated proteins (Fas, FADD, caspase‑8 and caspase‑3) and E‑cadherin in HCT‑116 cells were upregulated following treatment with curcumin in a dose‑dependent manner. By contrast, the expression of migration‑associated proteins, including MMP‑9, NF‑κB and claudin‑3, was downregulated with increasing curcumin concentrations. These data suggested that the inhibitory effect of curcumin on HCT‑116 cells may match that of 5‑FU. Therefore, curcumin induced cell apoptosis and inhibited tumor cell metastasis by regulating the NF‑κB signaling pathway, and its therapeutic effect may be comparable to t

Topics: Animals; Apoptosis; Cell Movement; Cell Proliferation; Colorectal Neoplasms; Curcumin; Fluorouracil; HCT116 Cells; Humans; Mice; NF-kappa B; Signal Transduction; Xenograft Model Antitumor Assays

Colorectal cancer (CRC) is the third most commonly occurring cancer in men and the second most commonly occurring cancer in women. Curcumin (CMN) is obtained from a natural source and has no toxicity, even at high doses (8,000 mg/kg body weight in 24 hours) and was determined to have anticancer potency on several kinds of carcinoma. However, its medical applications were limited because of its low solubility and poor bioavailability.. To improve the medical applications of CMN, various hydrophilic carriers such as poloxamer 407 (PMX-407), poloxamer 188 (PMX-188), Gelucire 50/13 (Gel-50/13), and mannitol (MNL) were used to prepare a binary complex solid dispersion (SD). These binary SDs were characterized for aqueous solubility in various solvents. Physical stability, thermal behaviors, and morphology were determined by Fourier transform infrared spectrophotometric analysis, powder X-ray diffraction analysis, thermogravimetric analysis, differential scanning calorimetric analysis, scanning electron microscopy, dynamic light scattering study, and the novel dyeing test. In vitro drug release was determined by dissolution study. Based on the characterization, the better SD complex was optimized using Box-Behnken design (BBD). The cytotoxicity and apoptosis study of prepared CMN (C-SD) were used to test for colorectal adenocarcinoma cell lines.. These results showed that the solubility of CMN is greatly improved after complexation with PXM-407 in SD. CMN is practically insoluble in water at acidic and neutral pH; however, the SD of CMN with PXM-407 produced significant improvement in solubility (1.266±0.0242 mg/mL) and dissolution (91.36±0.431% at 30 minutes); similarly, these data fit with a phase solubility study and in silico molecular modeling. Moreover, the solid-state characterization revealed that the SD complex exhibits the intermolecular hydrogen bond with drug and carrier. Also, the complex does not undergo any chemical modification owing to the amorphous form, and the dye test showed better coloring impact indicating the solubility of CMN. The cell cycle arrest confirmed at G2/M phase from flow cytometry analysis, and Western blot investigation was recognized molecular level cell death and the complex induced more exploit DNA during apoptosis.. This study confirmed that the ideal stoichiometric ratio of CMN with carrier to enhance its solubility was 1:1. This molecular complex of PXM-407 was found to be more effective against colorectal cancer (CRC) than pure CMN.

Topics: Adenocarcinoma; Antineoplastic Agents; Apoptosis; Cell Proliferation; Cell Survival; Colorectal Neoplasms; Curcumin; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Models, Molecular; Molecular Structure; Solubility; Structure-Activity Relationship; Tumor Cells, Cultured

Colorectal cancer (CRC) is a prevalent and fatal cancer. Oral administration provided the potential for in situ treatment of the colorectal cancer. However, drugs couldn't be well-absorbed mainly due to its degradation in the gastric area and poor intestinal permeability. In this study, we synthesized deoxycholic acid and hydroxybutyl decorated chitosan nanoparticles (DAHBC NPs) as oral curcumin (CUR) delivery system for colorectal cancer treatment. DAHBC with lower critical solution temperature (LCST) below 37 °C (27-33 °C) was obtained. DAHBC NPs were correspondingly stable in simulated gastric conditions (pH 1.2, 37 °C), due to the offset of size change between pH-responsive expansion and thermo-responsive shrinkage. In simulated intestinal tract (pH 7.0-7.4, 37 °C), DAHBC NPs exhibited burst release of CUR owing to the onefold effect of thermo-responsive shrinkage. DAHBC27 NPs showed the minimum CUR leakage (~10%) in simulated gastric conditions, because a furthest temperature-sensitive shrinkage caused by the lowest LCST offset the expansion in acid environment. DAHBC27 NPs induced ~10-fold increased (P < 0.05) CUR absorption by paracellular transport pathway, compared to the free CUR. Thus, DAHBC NPs stabilized in the gastric environment may be a promising oral drugs delivery system for effective in situ colorectal cancer therapy.

Topics: Administration, Oral; Adsorption; Caco-2 Cells; Chitosan; Colorectal Neoplasms; Curcumin; Deoxycholic Acid; Drug Carriers; Drug Liberation; Drug Stability; Gastric Mucosa; Hemolysis; Humans; Intestinal Absorption; Materials Testing; Nanoparticles; Temperature

Curcumin, a major yellow pigment and spice in turmeric and curry, has been demonstrated to have an anticancer effect in human clinical trials. Mutation of KRAS has been shown in 35%-45% of colorectal cancer, and regorafenib has been approved by the US FDA to treat patients with colorectal cancer. Synthetic lethality is a type of genetic interaction between two genes such that simultaneous perturbations of the two genes result in cell death or a dramatic decrease of cell viability, while a perturbation of either gene alone is not lethal. Here, we reveal that curcumin significantly enhanced the growth inhibition of regorafenib in human colorectal cancer HCT 116 cells (KRAS mutant) to a greater extent than in human colorectal cancer HT-29 cells (KRAS wild-type), producing an additive or synergistic effect in HCT 116 cells and causing an antagonistic effect in HT-29 cells. Flow cytometric analysis showed that the addition of curcumin elevated apoptosis and greatly increased autophagy in HCT 116 cells but not in HT-29 cells. Mechanistically, curcumin behaved like MEK-specific inhibitor (U0126) to enhance regorafenib-induced growth inhibition, apoptosis and autophagy in HCT 116 cells. Our data suggest that curcumin may target one more gene other than mutant KRAS to enhance regorafenib-induced growth inhibition (synthetic lethality) in colorectal cancer HCT 116 cells, indicating a possible role of curcumin in regorafenib-treated KRAS mutant colorectal cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Butadienes; Colorectal Neoplasms; Curcumin; Gene Expression Regulation, Neoplastic; HCT116 Cells; HT29 Cells; Humans; MAP Kinase Kinase Kinases; Mutation; Nitriles; Phenylurea Compounds; Protein Kinase Inhibitors; Proto-Oncogene Proteins p21(ras); Pyridines

Topics: Administration, Oral; Animals; Apoptosis; Azoxymethane; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Colitis; Colorectal Neoplasms; Curcumin; Cytokines; Dextran Sulfate; Disease Models, Animal; Disease Progression; Drug Synergism; Female; Inflammation; Inflammation Mediators; Intestines; Irinotecan; Macrophages; Mice; Mice, Inbred C57BL; Nanoparticles; RAW 264.7 Cells

Natural polyphenol Calebin A has been recently discovered as a novel derivate from turmeric with anti-cancer potential. Pro-inflammatory cytokine TNF-β (lymphotoxin α) is a stimulant for cancer cell malignity via activation of NF-B pathway, also in colorectal cancer (CRC). Here, we investigated the potential of Calebin A to suppress TNF-β-induced NF-B signalling in CRC.. Three distinct CRC cell lines (HCT116, RKO, SW480) were treated in monolayer or 3-dimensional alginate culture with TNF-β, Calebin A, curcumin, BMS-345541, dithiothreitol (DTT) or antisense oligonucleotides-(ASO) against NF-B.. Calebin A suppressed dose-dependent TNF-β-induced CRC cell vitality and proliferation in monolayer culture. Further, in alginate culture, Calebin A significantly suppressed TNF-β-enhanced colonosphere development, as well as invasion and colony formation of all three CRC cell lines investigated. Calebin A specifically blocked TNF-β-induced activation and nuclear translocation of p65-NF-B, similar to curcumin (natural NF-B inhibitor), BMS-345541 (specific IKK inhibitor) and ASO-NF-B. Moreover, Immunofluorescence and Immunoblotting showed that Calebin A, similar to curcumin or BMS-345541 suppressed TNF-β-induced activation and nuclear translocation of p65-NF-B and the transcription of NF-B-promoted biomarkers associated with proliferation, migration and apoptosis, in a dose- and time-dependent manner. Those findings were potentiated by the specific treatment of extracted nuclei with DTT, which abrogated Calebin A-mediated nuclear p65-NF-B-inhibition and restored p65-NF-B-activity in the nucleus.. Overall, these results demonstrate, for the first time, that multitargeted Calebin A has an anti-cancer capability on TNF-β-induced malignities through inhibitory targeting of NF-B activation in the cytoplasm, as well as by suppressing the binding of p65-NF-B to DNA.

Topics: Apoptosis; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cinnamates; Colorectal Neoplasms; Curcuma; Curcumin; Humans; Imidazoles; Lymphotoxin-alpha; Monoterpenes; Neoplasm Invasiveness; Neoplasm Metastasis; Quinoxalines; Signal Transduction; Transcription Factor RelA

High-fat diets (HFDs) and adiposity increase colorectal cancer risk, in part by elevating pro-inflammatory cytokines that activate pro-cancerous signaling pathways. Curcumin (CUR), a dietary polyphenol and salsalate (SAL), an non-steroidal anti-inflammatory drug (NSAID) lacking the gastrotoxicity of aspirin, each suppress inflammatory signaling, but via different cellular pathways.. A/J mice (n = 110) are fed a low-fat diet (LFD, 10% kcal), a HFD (60% kcal), a HFD containing 0.4% CUR, a HFD containing 0.3% SAL, or a HFD containing both agents (CUR/SAL). All mice receive six injections of azoxymethane. Compared to LFD-fed mice, HFD-fed mice display elevated colonic cytokines, crypt cell proliferation, and increased tumorigenesis (p < 0.05). CUR/SAL significantly reduces colonic cytokines (p < 0.01), suppresses activation of the PI3K/Akt/mTOR/NF-κB/Wnt pathways (p < 0.01), activates AMPK (p < 0.01), attenuates abnormal proliferation of the colonic mucosa (p < 0.05), and reduces tumor multiplicity and burden (p < 0.05), in comparison to the HFD control. In contrast, CUR or SAL alone does not suppress abnormal crypt cell proliferation or tumor multiplicity, and is largely ineffective in modifying activation of these signaling pathways.. These observations demonstrate the superiority of the CUR/SAL over the individual agents and provide a scientific basis for future translational studies in obese subjects and/or those habitually consuming HFDs.

Topics: Adiposity; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Proliferation; Colitis; Colorectal Neoplasms; Curcumin; Diet, High-Fat; Intestinal Mucosa; Male; Mice, Inbred Strains; Obesity; Precancerous Conditions; Salicylates; Signal Transduction

Irinotecan (CPT‑11) is a DNA topoisomerase I inhibitor which is widely used in clinical chemotherapy, particularly for colorectal cancer treatment. However, late‑onset diarrhea is one of the severe side‑effects of this drug and this restricts its clinical application. The present study aimed to investigate the protective effects of curcumin treatment on CPT‑11‑induced intestinal mucosal injury both in vitro and in vivo and to elucidate the related mechanisms involved in these effects. For this purpose, mice were intraperitoneally injected with CPT‑11 (75 mg/kg) for 4 days to establish a model of late‑onset diarrhea. Curcumin (100 mg/kg) was intragastrically administered 8 days before the injection of CPT‑11. Injury to small intestinal tissues was examined by H&E staining. The protein expression of prolyl 4‑hydroxylase subunit beta (P4HB) and peroxiredoxin 4 (PRDX4) was detected by immunohistochemistry, as well as western blot analysis. IEC‑6 cell viability was detected by MTT assay. Flow cytometry was performed to examine the cell apoptotic rate, mitochondrial membrane potential and reactive oxygen species (ROS) generation. Immunofluorescence was used to observe the localization of nuclear factor (NF)‑κB. The levels of cleaved caspase‑3, glucose‑regulated protein, 78 kDa (GRP78), P4HB, PRDX4 and CHOP were detected by western blot analysis. The results revealed that in vivo, curcumin effectively attenuated the symptoms of diarrhea and abnormal intestinal mucosa structure induced by CPT‑11 in nude mice. Treatment with curcumin also increased the expression of P4HB and PRDX4 in the tissue of the small intestine. In vitro, curcumin, exhibited little cytotoxicity when used at concentrations <2.5 µg/ml for 24 h in IEC‑6 cells. At this concentration, curcumin also improved cell morphology, inhibited apoptosis, maintained mitochondrial membrane potential and reduced the elevated levels of ROS induced by CPT‑11 (20 µg/ml). Furthermore, curcumin abolished NF‑κB signal transduction and protected the cells from CPT‑11‑induced apoptosis by upregulating the expression of molecular chaperones, such as GRP78, P4HB and PRDX4, and suppressing the levels of the apoptosis‑related proteins, CHOP and cleaved caspase‑3. On the whole, our data indicate that curcumin exerted protective effects against CPT‑11‑induced intestinal mucosa injury. The protective effects of curcumin are mediated by inhibiting the activation of NF‑κB, and suppressing oxidative stress and endoplasmic reti

Topics: Animals; Apoptosis; Cell Line; Colorectal Neoplasms; Curcumin; Diarrhea; Disease Models, Animal; Drug Evaluation, Preclinical; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Epithelial Cells; Humans; Injections, Intraperitoneal; Intestinal Mucosa; Irinotecan; Male; Mice; Mice, Inbred BALB C; Mice, Nude; NF-kappa B; Oxidative Stress; Rats; Signal Transduction; Topoisomerase I Inhibitors; Treatment Outcome

Curcumin (CUR) is a natural extract from the plant Curcuma longa and part of turmeric, a spice and herbal remedy in traditional medicine. Thousands of papers claim a plethora of health benefits by CUR, but a growing number of reports and contributions caution that many experimental data may be artifacts or outright deny any suitability of CUR due to its problematic physicochemical properties. Two major issues often encountered with CUR are its extraordinarily low solubility in water and its limited chemical stability. Here, we report on a novel nanoformulation of CUR that enables CUR concentrations in water of at least 50 g/L with relative drug loadings of >50 wt% and high dose efficacy testing in 3D tumor models. Despite this high loading and concentration, the CUR nanoformulation comprises polymer-drug aggregates with a size <50 nm. Most interestingly, this is achieved using an amphiphilic block copolymer, that by itself does not form micelles due to its limited hydrophilic/lipophilic contrast. The ultra-high loaded nanoformulations exhibit a very good stability, reproducibility and redispersibility. In order to test effects of CUR in conditions closer to an in vivo situation, we utilized a 3D tumor test system based on a biological decellularized tissue matrix that better correlates to clinical results concerning drug testing. We found that in comparison to 2D culture, the invasively growing breast cancer cell line MDA-MB-231 requires high concentrations of CUR for tumor cell eradication in 3D. In addition, we supplemented a 3D colorectal cancer model of the malignant cell line SW480 with fibroblasts and observed also in this invasive tumor model with stroma components a decreased tumor cell growth after CUR application accompanied by a loss of cell-cell contacts within tumor cell clusters. In a flow bioreactor simulating cancer cell dissemination, nanoformulated CUR prevented SW480 cells from adhering to a collagen scaffold, suggesting an anti-metastatic potential of CUR. This offers a rationale that the presented ultra-high CUR-loaded nanoformulation may be considered a tool to harness the full therapeutic potential of CUR.

Topics: Animals; Antineoplastic Agents; Cell Line; Cell Survival; Colorectal Neoplasms; Curcumin; Drug Carriers; Humans; Micelles; Nanoparticles; Swine

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Colorectal Neoplasms; Curcuma; Curcumin; Down-Regulation; Drug Resistance, Neoplasm; Fluorouracil; Gene Expression Regulation, Neoplastic; Genes, myc; Humans; Insulin; Plant Extracts; Receptor, IGF Type 1; Receptors, Somatomedin

Colorectal cancer (CRC) represents the third most diagnosed type of cancer worldwide with high mortality and an increased incidence rate. Bioactive dietary components such as curcumin and resveratrol have great therapeutic potential as they can modulate a plethora of signaling pathways related to colorectal carcinogenesis. Previous data have demonstrated that curcumin and resveratrol can induce apoptosis in different types of cancer cells. Considering the lack of data on the combinatorial effect of curcumin and resveratrol associated with the induction of apoptosis in colorectal pathology, the main objective of this study is to investigate the impact of single vs. combinatorial treatment of resveratrol and curcumin on their cytotoxic effects, as well as the modulation of several essential pro-apoptotic genes, on two colorectal cancer cell lines (DLD-1 and Caco-2) different in terms of chromosomal stability (MSI and MSS). The cytotoxic effects were evaluated by the MTT assay, the nature of the interaction between curcumin and resveratrol was assessed by the combination index method and the expression levels of key genes involved in the modulation of pro-apoptotic mechanisms were evaluated by RT-qPCR. Our data indicate that the combination treatment of curcumin and resveratrol is more effective in inhibiting the proliferation in a dose-dependent manner, with a synergistic effect for the DLD-1 cell line (CI < 1) and an additive effect for the Caco-2 cell line (CI ≥ 1). The IC50 values for the combination treatment were 71.8 μM (20.5 μM curcumin + 51.3 μM resveratrol) for the DLD-1 cell line and 66.21 μM (18.9 μM curcumin + 47.3 μM resveratrol) for the Caco-2 cell line, respectively. Our data pointed out, for the first time, that several genes involved in the modulation of apoptosis, including PMAIP1, BID, ZMAT3, CASP3, CASP7, and FAS, represent new targets of both singular and combinatorial treatments with resveratrol and curcumin, and also the combinatorial approach of curcumin and resveratrol exhibits a more powerful gene regulating effect compared to single treatment. Considering the beneficial aspects of the combinatorial approach with curcumin and resveratrol on colorectal cancer cells further studies should address the possible pharmacological benefits of using a combination of both dietary agents with different chemotherapeutic drug approaches.

Topics: Apoptosis; Apoptosis Regulatory Proteins; Caco-2 Cells; Cell Line, Tumor; Colorectal Neoplasms; Curcumin; Drug Synergism; Humans; Resveratrol

MicroRNAs (miRNAs) play a key role on gene expression regulation contributing to cell homeostasis, and they are highly dysregulated in cancer. Consequently, miRNA-based therapies are an attractive approach to develop novel anticancer strategies. The main objective of this work was to explore the full potential of protamine nanocapsules (Pr NCs) to develop an anticancer therapy based on the restoration of oncosuppressor miR-145, downregulated in colorectal cancer cells. The composition of Pr NCs was defined based on the selection of surfactants, and protamine that would enable an efficient association and intracellular delivery of miRNA mimics according to the layer-by-layer approach, and the encapsulation of curcumin within the oily core. After exposure of colorectal cancer cells with (i) miR-145 and (ii) curcumin-loaded Pr NCs, a strong increase in the intracellular levels of miR-145, which translated into a decreased cell proliferation rate and migration capacity of the treated cells, was observed. The potential of exploiting Pr NCs for the co-delivery of both biomolecules, miRNAs and curcumin, has also been proved. All together, here we evaluate the possibility to use Pr NCs to efficiently increase the intracellular levels of the oncosuppressor miR-145.

Topics: Cell Line, Tumor; Cell Movement; Cell Proliferation; Colorectal Neoplasms; Curcumin; Down-Regulation; Drug Carriers; Humans; MicroRNAs; Nanocapsules; Protamines

Paternally expressed gene-10 (PEG10) could participate in several carcinomas and might be regulated by miR-491. To now, miR-491 was found to play an important role in the sensitivity and mechanism of drug usage in the treatment of colorectal cancer, and drug resistance is a key factor to affect the disease healing. In this study, miR-491, PEG10, Wnt1, and β-catenin expression levels and their correlation with colorectal cancer were assessed in cancer tissues and adjacent parts. And the target relationship between PEG10 and miR-491 was verified. Meanwhile, the impaction of Curcumin on miR-491, PEG10, and Wnt/β-catenin signaling pathway were analyzed in HCT-116 cells. The effects of PEG10 and Curcumin on human HCT-116 cells proliferation and apoptosis were investigated by MTT and flow cytometry assay. Results showed that the expression of miR-491 in colon cancer tissues was decreased, but PEG10, Wnt1, and β-catenin were higher than that in adjacent tissues. The PEG10 gene 3' UTR could combine with miR-491 seed sequence and miR-491 overexpression could cause a decrease in PEG10, Wnt1, and β-catenin levels in human HCT-116 cells. Furthermore, PEG10 overexpression increased the expression levels of Wnt1 and β-catenin, thereby promoting cell proliferation and inhibiting apoptosis. In addition, Curcumin could up-regulate miR-491, inhibit PEG10, and Wnt/β-catenin signaling pathway. Consequently, Curcumin reduced HCT-116 cells proliferation and promoted cells apoptosis via the miR-491/PEG10 pathway. In conclusion, PEG10 was a target gene of miR-491, miR-491/PEG10 strengthen the sensitivity of Curcumin in HCT-116 cells proliferation and apoptosis, which might act as an ideal diagnostic biomarker treatment methods.

Topics: Aged; Antineoplastic Agents; Apoptosis Regulatory Proteins; Biomarkers, Tumor; Cell Proliferation; Cell Survival; Colorectal Neoplasms; Curcumin; DNA-Binding Proteins; Female; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humans; Male; MicroRNAs; Middle Aged; Proteins; RNA-Binding Proteins; Wnt Signaling Pathway

Colorectal cancer, also known as bowel cancer, is the uncontrolled cell growth in the colon or rectum (parts of the large intestine), or in the appendix. The colon specific drug delivery would alleviate the systemic side effects and would assure the safe therapy for colonic disorders with minimum dose and duration of therapy. The liquisolid technique refers to solubilisation of drug in a non-volatile solvent combined with inclusion of appropriate carrier and coating agent required for tableting. Colon specific degradation of natural polymer, guar gum and pH dependant degradative (pH-7) property of eudragit L100 restricts the delivery of curcumin in gastric and intestinal pH. Formulated curcumin liquisolid powder was evaluated for the micrometric properties, solubility and by differential thermal analysis, X ray powder diffraction and scanning electron microscopy. Curcumin loaded liquisolid tablet showed more anticancer activity against HCT-15 compared with free curcumin. Bioavailability study of the coated and uncoated liquisolid tablets were performed using Newzealand white rabbits. The present study concludes that liquisolid technique is a promising alternative for improving oral bioavailability and dissolution rate of water insoluble drug and coating liquisolid tablet with colon sensitive polymers showed site specific release of drug in the colon.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Colon; Colorectal Neoplasms; Curcumin; Humans; Polymethacrylic Acids; Rabbits; Tablets, Enteric-Coated

Signal transducers and activators of transcription 3 (STAT3) represent a transcription factor that is constitutively activated in various cancers. Numerous studies have shown that STAT3 plays crucial roles in cell proliferation and survival, angiogenesis, tumor-promoting inflammation, and suppression of antitumor host immune response in the tumor microenvironment. In this study, we investigated a novel inhibitor, called -6b, to target STAT3 in colorectal cancer cells. The influence of 5Br-6b on the proliferation of colorectal cell lines SW480 and HCT116 was evaluated using an 3-(4, 5-dimethylthiazolyl)-2 and 5-diphenyltetrazolium bromide assay. We detected cell apoptosis after the treatment of 5Br-6b by flow cytometry. In addition, 5Br-6b caused the cleavage of caspase-3 and decreased the expression of Bcl-2. Cancer cell invasion and migration were measured by transwell and wound-healing assay. The potential mechanism was evaluated by western blotting and immunofluorescence. The results show that 5Br-6b inhibits the activation of STAT3, and decreases the expression of its target genes that regulate cell proliferation, migration, and apoptosis. Thus, 5Br-6b is a promising therapeutic drug candidate for colorectal cancer by inhibiting persistent STAT3 signaling.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Movement; Cell Proliferation; Colorectal Neoplasms; Curcumin; Drug Screening Assays, Antitumor; HCT116 Cells; Humans; STAT3 Transcription Factor

Colorectal-cancer (CRC) is the third leading cause of death due to cancer, supporting the need for identification of novel anticancer drug to improve the efficacy of current-therapy. There is growing bodies of data showing the antitumor-activity of curcumin, although it is associated with low absorption. The aim of current study was explored the therapeutic-potential of novel phytosomal curcumin as well as its application in combination with 5-Flurouracil (5-FU) in a mouse-model of colitis-associated colon-cancer. The anti-proliferative-activity of phytosomal curcumin was assessed in 2- and 3-dimensional cell-culture-models as well as in a mouse-model of colitis-associated colon-cancer. The expression-levels of CyclinD1, beclin, E-cadherin, and p-GSK3a/b were investigated by qRT-PCR and/or Western-blotting. We evaluated the anti-inflammatory of this agent by pathological-evaluation and disease-activity-index (DAI). Moreover, oxidant/antioxidant activity was examined by malondialdehyde (MDA), total-thiols (T-SH), superoxide-dismutase (SOD), and catalase (CAT) activity parameters. Our data showed that phytosomal curcumin and its combination with 5-FU inhibited cell growth and invasive behavior of CRC cells through modulation of Wnt-pathway and E-cadherin. Combination of curcumin with 5-FU dramatically reduced the tumor-number and tumor-size in both distal and middle parts of colon in colitis-associated colon cancer followed by reduction in DAI. Also, curcumin suppressed the colonic inflammation and notably recovered the increased levels of MDA, decreased thiol level and reduced activity of CAT. We demonstrated the antitumor-activity of novel form of curcumin in CRC, supporting further investigations on the therapeutic-potential of this approach in colorectal-cancer.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Colitis; Colonic Neoplasms; Colorectal Neoplasms; Curcumin; Humans; Mice, Inbred C57BL; Signal Transduction

On the basis of preliminary in vitro experience, we assessed whether an enriched nutritional formulation with estrogen receptor (ER)-beta agonist and anti-inflammatory properties may prevent inflammation-associated colorectal cancer (CRC) in an animal model. Study sample enclosed 110 C57BL/6J male mice. Forty underwent dietary supplement safety assessment (20 standard diet and 20 enriched formulation). Seventy were treated with azoxymethane (AOM)/dextran sulfate sodium and divided into two groups: 35 received standard diet and 35 enriched formulation (curcumin, boswellic acids, silymarin and maltodextrins). Miniature colonoscopy demonstrated colitis and solid lesion development in five mice/group 100 days after first AOM injection. Mice were killed after 10 days. In each group, four subgroups received intraperitoneal bromodeoxyuridine (BrdU) injection at 24th/48th/72nd/96th hour before killing. Anti-inflammatory effect and chemoprevention were evaluated by lesion number/size, histological inflammation/dysplasia/neoplasia assessment, pro-inflammatory cytokine messenger RNA (mRNA), ER-beta/ER-alpha/BrdU immunohistochemistry and TUNEL immunofluorescence. Standard formulation assumption was associated with colon shortening compared with enriched one (P = 0.04), which reduced solid lesion number and size (P < 0.001 for both), histological inflammation score (P = 0.04), pro-inflammatory cytokine mRNA expression (P < 0.001), number of low-grade dysplasia (LGD; P = 0.03) and high-grade dysplasia (P < 0.001) areas. CRC was observed in 69.6% in standard and 23.5% in enriched formulation assuming animals (P < 0.001). Enriched formulation induced lower ER-alpha expression in CRC (P < 0.001) and higher ER-beta expression in LGD (P < 0.001) being associated to higher epithelial turnover (BrdU; P<0.001) in normal mucosa and increased apoptosis in LGD and CRC (P < 0.001 for both). Our results are promising for a successful anti-inflammatory and chemopreventive effect of enriched formulation in CRC arising from inflamed tissue.

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Azoxymethane; Chemoprevention; Colitis; Colon; Colonoscopy; Colorectal Neoplasms; Curcumin; Cytokines; Dextran Sulfate; Disease Models, Animal; Food, Fortified; Immunohistochemistry; Male; Mice; Mice, Inbred C57BL; Polysaccharides; Real-Time Polymerase Chain Reaction; Receptors, Estrogen; Silymarin; Triterpenes

Curcumin, a well-studied component in turmeric, exhibits potent antitumor effects in colorectal cancer. Previous studies showed that turmerones raised the accumulation of curcumin inside colonic cells, and curcumin present in turmeric ethanolic extract had enhanced anti-tumor activities in mice. Metastasis accounts for more than 90% colorectal cancer deaths. However, the anti-metastatic effect of turmeric extract on colorectal cancer is still unknown.. In the present study, colony formation, scratch, transwell and Western blot were used to assess colony formation, motility, migration and underlying mechanisms in vitro, respectively. Anti-tumor and anti-metastatic effects in vivo were investigated using an orthotopic xenograft model.. Turmeric extract exhibited cytotoxic effect, inhibited colony formation, decreased cell motility, migration and epithelial-mesenchymal transitions through regulating multiple pathways including cofilin, FAK/p-Src, AKT, Erk and STAT3 signaling pathways in murine colorectal cancer cells. Furthermore, turmeric extract at 200 mg/kg could decrease colon tumor burden and inhibit liver and lung metastasis in vivo. Treatment of turmeric extract enhanced immunity through T cell stimulation, changed tumor microenvironment, exerted anti-metastatic effects which were shown for the first time in pre-clinical colorectal cancer models. The decrease of immunity after FOLFOX treatment was also firstly demonstrated in mouse model.. Turmeric extract was demonstrated for the first time for its anti-tumor and anti-metastatic effects in both colorectal cancer cells and orthotopic mouse model through regulation of multiple targets. These findings strongly suggested the promising use of turmeric extract as chemopreventive or chemotherapeutic agent for colorectal cancer patients with metastasis.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Colorectal Neoplasms; Curcuma; Curcumin; Fluorouracil; Humans; Male; Mice; Mice, Inbred BALB C; Plant Extracts; Signal Transduction; Tumor Burden; Xenograft Model Antitumor Assays

Combining anti-cancer agents in cancer therapies is becoming increasingly popular due to improved efficacy, reduced toxicity and decreased emergence of resistance. Here, we test the hypothesis that dietary agents such as oligomeric proanthocyanidins (OPCs) and curcumin cooperatively modulate cancer-associated cellular mechanisms to inhibit carcinogenesis. By a series of in vitro assays in colorectal cancer cell lines, we showed that the anti-tumorigenic properties of the OPCs-curcumin combination were superior to the effects of individual compounds. By RNA-sequencing based gene-expression profiling in six colorectal cancer cell lines, we identified the cooperative modulation of key cancer-associated pathways such as DNA replication and cell cycle pathways. Moreover, several pathways, including protein export, glutathione metabolism and porphyrin metabolism were more effectively modulated by the combination of OPCs and curcumin. We validated genes belonging to these pathways, such as HSPA5, SEC61B, G6PD, HMOX1 and PDE3B to be cooperatively modulated by the OPCs-curcumin combination. We further confirmed that the OPCs-curcumin combination more potently suppresses colorectal carcinogenesis and modulated expression of genes identified by RNA-sequencing in mice xenografts and in colorectal cancer patient-derived organoids. Overall, by delineating the cooperative mechanisms of action of OPCs and curcumin, we make a case for the clinical co-administration of curcumin and OPCs as a treatment therapy for patients with colorectal cancer.

Topics: Animals; Anticarcinogenic Agents; Carcinogenesis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Colorectal Neoplasms; Curcumin; Drug Interactions; Endoplasmic Reticulum Chaperone BiP; Humans; Mice; Organoids; Polymerization; Proanthocyanidins; Safety; Xenograft Model Antitumor Assays

Multidrug resistance (MDR) is a major concern when using chemotherapy for the treatment of patients with colorectal cancer. MDR modulators are agents that can reverse MDR and, thus, enhance the chemosensitivity of tumor cells. The development of MDR modulators can improve the therapeutic efficacies of MDR in cancer. However, few effective MDR modulators have been identified so far. Curcumin has been reported to be an effective compound in the reversal of MDR in colorectal cancer cells. However, the mechanisms associated with the reversal effect of curcumin on MDR and its regulation of target factors in MDR cells remain to be fully elucidated. 3‑(4,5‑dimethyl‑2‑thiazol)‑2,5‑diphenyltetrazolium bromide assays, flow cytometer apoptosis assays as well as mRNA and protein expression assays were performed in the present study, and the results confirmed the reversal effect of curcumin on HCT‑8/5‑Fu cells and provided evidence that activated nuclear factor erythroid 2‑related factor (Nrf2) deficiency induced by the curcumin altered the B‑cell lymphoma 2 (Bcl‑2) associated X protein/Bcl‑2 expression ratio, which led to the induction of apoptosis in HCT‑8/5‑Fu cells. These results indicated that Nrf2 may have a functional in the reversal effect of curcumin and contribute, at least in part, to the outcomes of chemotherapy in patients with MDR.

Topics: Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Curcumin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Fluorouracil; Genes, bcl-2; Humans; NF-E2-Related Factor 2; Signal Transduction

In-stent restenosis caused by tumor ingrowth is a major problem for patients undergoing stent placement because conventional stents often lack sustainable antitumor capabilities. The aim of this work is to develop a silk fibroin (SF)-based nanofibrous membrane that is loaded with combined-therapy drugs by using electrospinning technologies, which is further coated on a polydioxanone (PDO) stent and used for the treatment of colorectal cancer (CRC). In order to improve treatment effectiveness, a combination of therapeutic drugs, i.e., curcumin (CUR) and 5-fluorouracil (5-FU), is dissolved into SF solution and then eletrospun onto the surface of the PDO stent. The morphology, secondary structure, and in vitro drug release profiles of the membranes are characterized. The antitumor efficacy is assessed in vitro and in vivo using a human CRC cell line and normal cells, and tumor-bearing nude mice. In vitro and in vivo studies on the nanofibrous memembrane-coating demonstrate improved antitumor effects for the CUR/5-FU dual drug system which can be attributed to cell cycle arrest in the S phase in association with induced apoptosis in tumor cells by blocking signal transducer and activator of transcription3 (Stat3) and nuclear factor kappa beta (NF-kB) signaling pathways, suggesting potential in the treatment of CRC in the future.

Topics: Absorbable Implants; Animals; Antineoplastic Agents; Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Colorectal Neoplasms; Curcumin; Drug Liberation; Drug Therapy, Combination; Drug-Eluting Stents; Fibroins; Fluorouracil; Humans; Mice; Mice, Nude; Nanofibers; Polydioxanone; Surface Properties; Transplantation, Heterologous

The prime objective of current work was to develop a strategy for preparation of combinational nano-formulation for reversal of drug resistance.. As a model system, doxorubicin (DOX)-resistant COLO205 cells were developed and validated. From co-treatment studies with DOX, curcumin was selected as it reversed DOX-resistance at lowest concentration. In an attempt to increase its solubility, curcumin was encapsulated into hydroxypropyl-β-cyclodextrin (HP-β-CD). Here, we propose that presence of stabilizer overcomes its low encapsulation efficiency. Thus, we evaluated curcumin encapsulation in HP-β-CD in presence of different stabilizers and organic solvents. Finally, the effect of nanocurcumin with liposomal DOX was studied for reversal of resistance in COLO205 cells.. In the process encapsulation, selective optimization of organic solvent by freeze-drying was found to be appropriate among other methods. From optimization studies with different organic solvent (acetone and dichloromethane) and stabilizer [polyvinyl alcohol (PVA) and Pluronics], HP-β-CD-encapsulated curcumin prepared using acetone in PVA-stabilized dispersion increased encapsulation (60%) with size of ~40 nm. Prepared nano-curcumin reversed the DOX resistance effectively in combination with liposomal DOX.. Curcumin reversed DOX resistance in COLO205 cells at low concentration and enhanced curcumin encapsulation in HP-β-CD was noted in presence of PVA. Further, it was observed that prepared HP-β-CD-encapsulated curcumin is equi-efficacious to nano-dispersed curcumin.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Adenocarcinoma; Antibiotics, Antineoplastic; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cell Line, Tumor; Chemistry, Pharmaceutical; Colorectal Neoplasms; Curcumin; Doxorubicin; Drug Resistance, Neoplasm; Excipients; Humans; Nanoparticles; Particle Size; Polyethylene Glycols; Solubility; Solvents

Curcumin has proven to be a potent antitumor agent in both preclinical and clinical models of colorectal cancer (CRC). It has also been identified as a ligand of the transcription factor known as the aryl hydrocarbon receptor (AHR). Our laboratory has identified the AHR as a mechanism which contributes to both tumorigenesis in a mouse model of inflammatory CRC as well an apoptotic target in vitro. Curcumin's role as an AHR ligand may modulate its effects to induce colon cancer cell death, and this role may be enhanced via structural modification of the curcumin backbone. We sought to determine if the two piperidone analogs of curcumin, RL66 and RL118, exhibit more robust antitumor actions than their parent compound in the context of colorectal cancer in vitro. Moreover, to ascertain the ability of curcumin, RL66 and RL118 to activate the AHR and evaluate if this activation has any effect on CRC cell death.. DLD1, HCT116, LS513, and RKO colon cell lines were propagated in vitro. Natural curcumin was obtained commercially, whereas RL66 and RL118 were synthesized and characterized de novo. Multiwell fluorescent/luminescent signal detection was used to simultaneously ascertain cell viability, cell cytonecrosis, and relative amounts of apoptotic activity. AHR activity was measured with a dual luciferase reporter gene system. Stable expression of small interfering RNA interference was established in the HCT116 cell lines to create AHR "knock down" cell lines.. Both RL66 and RL118 proved to be more potent antitumor agents than their parent compound curcumin in all cell lines tested. The majority of this cell death was due to induction of apoptosis, which occurred earlier and to a greater degree following RL66 and RL118 treatment as opposed to curcumin. Also, RL66 and RL118 were found to be activators of AHR, and a portion of their ability to cause cell death was dependent on this induction. Curcumin was found unable to activate the AHR, and levels of AHR messenger RNA did not change their effects on cell death.. Piperidone analogs of curcumin exhibited enhanced antitumor effects in vitro as opposed to their parent compound. Even more, this enhanced cell death profile may be partially attributed to the ability of these compounds to activate the AHR. Further study of synthetic curcumin analogs as chemopreventives and chemoadjuncts in CRC is warranted. Also, more generally, the AHR may represent a potential putative target for novel anticancer agents for CRC.

Topics: Antineoplastic Agents; Apoptosis; Basic Helix-Loop-Helix Transcription Factors; Biomarkers, Tumor; Cell Survival; Colorectal Neoplasms; Curcumin; HCT116 Cells; Humans; Piperidones; Pyridines; Receptors, Aryl Hydrocarbon

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Curcumin; Drug Resistance, Neoplasm; Heat-Shock Proteins; HSP27 Heat-Shock Proteins; Humans; Inhibitor of Apoptosis Proteins; Molecular Chaperones; Proto-Oncogene Proteins c-bcl-2; Survivin

High-fat diets (HFDs) and excess adiposity increase proinflammatory cytokines in the colon, altering gene expression in a manner that promotes the development of colorectal cancer (CRC). Thus, compounds that reduce this biochemical inflammation are potential chemopreventive agents. Curcumin (CUR), a dietary polyphenol, and salsalate (SAL), a non-steroidal anti-inflammatory drug, are both anti-inflammatories. We investigated the inhibitory effects of CUR with or without SAL on inflammatory cytokines and procarcinogenic signaling in azoxymethane (AOM)-treated A/J mice. A sub-tumorigenic AOM dose was chosen to produce a biochemical and molecular procarcinogenic colonic environment without tumors. Mice were fed either a HFD (60% of kilocalories) or low-fat diet (LFD) (10% of kilocalories). One HFD treatment group received 0.2% CUR in the diet; one received 0.2% CUR + 0.15% SAL; and one received 0.4% CUR + 0.3% SAL. The HFD mice developed 30% greater fat mass than the LFD mice (p < 0.05). The colonic concentrations of interleukin-1β (IL-1β) and interleukin-6 (IL-6) in the HFD mice were decreased by 50-69% by the high-dose combination regimen (p < 0.015). Only the combination regimens significantly suppressed phosphorylation of protein kinase B (Akt) and nuclear factor-κB (NF-κB) p65 (p < 0.044). The combination of CUR and SAL reduces the concentration of proinflammatory cytokines and diminishes activation of Akt and NF-κB more effectively than CUR alone, providing a scientific basis for examining whether this combination mitigates the risk of CRC in obese individuals.

Topics: Animals; Anti-Inflammatory Agents; Azoxymethane; Colorectal Neoplasms; Curcumin; Diet, High-Fat; Humans; Interleukin-6; Male; Mice; NF-kappa B; Salicylates

Fucoxanthin (Fx), one of the major xanthophylls in brown algae, is known to be effective for colorectal cancer (CRC) chemoprevention through inhibiting cell growth, cell cycle and caspase activation. Recently, we observed fucoxanthinol (FuOH), an anti-cancer active metabolite of Fx, treatment of human CRC cells resulted in plenty of living floating cells several hours after exposure, and induced apoptosis. In the present study, we investigated whether FuOH induced anchorage-dependent apoptosis, that is "anoikis", along with integrin signal suppression in human CRC cells. We found that cells exposed to 2.5 μM FuOH clearly showed anti-proliferative and apoptotic effects to DLD-1 cells, human CRC cells. FuOH treatment of DLD-1 cells led to an increase in anoikis-like changes represented by Calcein AM negative/ethidium homodimer-1 positive cell and living floating cells. Moreover, FuOH decreased FAK activation, and altered integrin β1 expression and distribution after 6 h treatment. After 24 h, the cells decreased PPARγ expression and Akt activation and increased integrin β1 expression. Our findings suggested that FuOH can induce anoikis in CRC cells through suppression of integrin signals in human CRC cells.

Topics: Allyl Compounds; Anoikis; Antineoplastic Agents, Phytogenic; beta Carotene; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Curcumin; Dietary Supplements; Focal Adhesion Kinase 1; Gene Expression Regulation, Neoplastic; Humans; Integrin beta1; Isothiocyanates; Lipids; PPAR gamma; Sulfides; Sulfoxides

Chemoprevention is a practical approach to reduce the risk of various cancers including colorectal cancer (CRC). The goal is to reduce the incidence of pre-neoplastic adenomatous polyps and prevent its progression to CRC. Curcumin and silibinin prevent intestinal polyp formation in mice. Curcumin sensitizes silymarin to exert synergistic anticancer activity in colon cancer cells. Patients presenting with multiple colorectal adenomatous polyps (MCRA) have a high lifetime risk for CRC. We present a 57-year-old man with MCRA, without deleterious germline APC or MYH mutations. Our patient had 54 polyps in the first colonoscopy, most of 3 to 8 mm and one of 20 mm with high grade dysplasia / adenocarcinoma. Four subsequent colonoscopies showed continuous development of adenomatous polyps treated by polypectomy for the most part and some with heat. After the treatment with curcumin for 3 months and a half followed by silibinin for 9 months, we find many less polyps than in the previous colonoscopies, going from the finding of 40 adenomas of 3-6 mm in the pre-treatment colonoscopy to 3 polyps after treatment.

Topics: Antineoplastic Agents; Chemoprevention; Colorectal Neoplasms; Curcumin; Drug Therapy, Combination; Humans; Intestinal Polyps; Male; Middle Aged; Recurrence; Silybin; Silymarin

Although chemotherapy is the cornerstone treatment for patients with metastatic colorectal cancer (mCRC), acquired chemoresistance is common and constitutes the main reason for treatment failure. Monoclonal antibodies against insulin-like growth factor-1 receptor (IGF-1R) have been tested in pre-treated mCRC patients, but results have been largely deceiving.. We analysed time to progression, overall survival, and the mutational status of RAS, BRAF and nuclear p-IGF-1R expression by immunohistochemistry, in 470 metastatic CRC patients. The effect of IGF-1R activation and distribution was also assessed using cellular models of CRC and RNAi for functional validation.. Nuclear IGF-1R increased in metastatic tumours compared to paired untreated primary tumours, and significantly correlated with poor overall survival in mCRC patients. In vitro, chemo-resistant cell lines presented significantly higher levels of IGF-1R expression within the nuclear compartment, and PIAS3, a protein implicated also in the sumoylation process of intranuclear proteins, contributed to IGF-1R nuclear sequestration, highlighting the essential role of PIAS3 in this process. Intriguingly, we observed that ganitumab, an IGF-1R blocking-antibody used in several clinical trials, and dasatinib, an SRC inhibitor, increased the nuclear localisation of IGF-1R.. Our study demonstrates that IGF-1R nuclear location might lead to chemotherapy and targeted agent resistance.

Topics: Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cell Nucleus; Cell Survival; Cetuximab; Colorectal Neoplasms; Curcumin; Dasatinib; Drug Resistance, Neoplasm; Fatty Acids, Unsaturated; Female; Fluorouracil; Gene Silencing; HCT116 Cells; HT29 Cells; Humans; Leucovorin; Male; Middle Aged; Molecular Chaperones; Molecular Targeted Therapy; Niacinamide; Organoplatinum Compounds; Oxaliplatin; Panitumumab; Phenylurea Compounds; Protein Inhibitors of Activated STAT; Protein Transport; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Pyrimidines; Pyrroles; Receptor, IGF Type 1; Signal Transduction; Sorafenib

The transcription factor NF-κB plays a central role in angiogenesis in colorectal cancer (CRC). Curcumin is a natural dietary product that inhibits NF-κB. The objective of this study is to evaluate the antiangiogenic effects of curcumin and two potent synthetic analogues (EF31 and UBS109) in CRC. IC

Topics: Angiogenesis Inhibitors; Animals; Chickens; Colon; Colorectal Neoplasms; Curcumin; Female; HCT116 Cells; HT29 Cells; Human Umbilical Vein Endothelial Cells; Humans; Mice, Nude; Neovascularization, Pathologic; NF-kappa B; Piperidones; Pyridines; Rats; Rectum; Signal Transduction; Vascular Endothelial Growth Factor A

In the present study, we report the properties of a mucoadhesive chitosan-pectinate nanoparticulate formulation able to retain its integrity in the milieu of the upper gastrointestinal tract and subsequently, mucoadhere and release curcumin in colon conditions. Using this system, we aimed to deliver curcumin to the colon for the possible management of colorectal cancer. The delivery system comprised of a chitosan-pectinate composite nanopolymeric with a z-average of 206.0 nm (±6.6 nm) and zeta potential of +32.8 mV (±0.5 mV) and encapsulation efficiency of 64%. The nanoparticles mucoadhesiveness was higher at alkaline pH compared to acidic pH. Furthermore, more than 80% release of curcumin was achieved in pectinase-enriched medium (pH 6.4) as opposed to negligible release in acidic and enzyme-restricted media at pH 6.8. SEM images of the nanoparticles after exposure to the various media indicate a retained matrix in acid media as opposed to a distorted/fragmented matrix in pectinase-enriched medium. The data strongly indicates that the system has the potential to be applied as a colon-targeted mucoadhesive curcumin delivery system for the possible treatment of colon cancer.

Topics: Antineoplastic Agents; Biocompatible Materials; Chitosan; Colon; Colorectal Neoplasms; Curcumin; Drug Carriers; Drug Delivery Systems; Humans; Nanoparticles

(E)-1-(3'-fluoro-[1,1'-biphenyl-3-yl)-3-(3-hydroxy-4-methoxyphenyl)prop-2-en-1-one) (MC37), a novel mono-carbonyl curcumin analog, was previously synthesized in our laboratory as a nuclear factor kappa B (NF-κB) inhibitor with excellent cytotoxicity against several cancer cell lines. In this study, our further investigations showed that the potent growth inhibitory activity of MC37 in human colorectal cancer cells was associated with the arrest of cell cycle progression and the induction of apoptosis. As a multi-targeted agent, MC37 inhibited the intracellular microtubule assembly, altered the expression of cyclin-dependent kinase 1 (CDK1), and ultimately induced G2/M cell cycle arrest. Moreover, MC37 collapsed the mitochondrial membrane potential (MMP), increased the Bax/Bcl-2 ratio, activated the caspase-9/3 cascade, and finally led to cancer cells apoptosis, suggesting that the mitochondrial-mediated apoptotic pathway was involved in MC37-induced apoptosis. In conclusion, these observations demonstrated that mono-carbonyl curcumin analogs would serve as multi-targeted lead for promising anti-colorectal cancer agent development.

Topics: Antineoplastic Agents; Apoptosis; Biphenyl Compounds; Caspase 3; Caspase 9; Cell Line, Tumor; Colorectal Neoplasms; Curcumin; Enzyme Activation; G2 Phase Cell Cycle Checkpoints; Gene Expression Regulation, Neoplastic; Humans; M Phase Cell Cycle Checkpoints; Membrane Potential, Mitochondrial; Microtubules; Mitochondria; Propane; Proto-Oncogene Proteins c-bcl-2

Colorectal cancer (CRC) is a major cause of cancer morbidity and mortality worldwide. Although response rates and overall survival have been improved in recent years, resistance to multiple drug combinations is inevitable. Therefore, the development of more efficient drugs, with fewer side effects is urgently needed. To this end, we have investigated in the present report the effect of PAC, a novel cucumin analogue, on CRC cells both in vitro and in vivo. We have shown that PAC induces apoptosis, mainly via the internal mitochondrial route, and inhibits cell proliferation through delaying the cell cycle at G2/M phase. Interestingly, the pro-apoptotic effect was mediated through STAT3-dependent down-regulation of cyclin D1 and its downstream target survivin. Indeed, change in the expression level of cyclin D1 modulated the expression of survivin and the response of CRC cells to PAC. Furthermore, using the ChIP assay, we have shown PAC-dependent reduction in the binding of STAT3 to the cyclin D1 promoter in vivo. Additionally, PAC suppressed the epithelial-to-mesenchymal process through down-regulating the mesenchymal markers (N-cadherin, vimentin and Twist1) and inhibiting the invasion/migration abilities of the CRC cells via repressing the pro-migration/invasion protein kinases AKT and ERK1/2. In addition, PAC inhibited tumor growth and repressed the JAK2/STAT3, AKT/mTOR and MEK/ERK pathways as well as their common downstream effectors cyclin D1 and survivin in humanized CRC xenografts. Collectively, these results indicate that PAC has potent anti-CRC effects, and therefore could constitute an effective alternative chemotherapeutic agent, which may consolidate the adjuvant treatment of colon cancer.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Proliferation; Colon; Colorectal Neoplasms; Curcumin; Cyclin D1; Epithelial-Mesenchymal Transition; G2 Phase Cell Cycle Checkpoints; HCT116 Cells; Humans; M Phase Cell Cycle Checkpoints; Mice, Nude; Rectum; Signal Transduction; STAT3 Transcription Factor

Colorectal cancer is a critical health concern because of its incidence as the third most prevalent cancer in the world. Currently, 5-fluorouracil (5-FU), 6-thioguanine, and certain other genotoxic agents are mainstays of treatment; however, patients often die due to emergence of resistant population. Curcumin, a bioactive compound derived from the dietary turmeric (Curcuma longa) is an effective anticancer, anti-inflammatory, and antioxidant agent. Previously, we reported that human colorectal cancer cell lines compromised for mismatch repair (MMR) function exhibit heightened sensitivity to curcumin due to sustained curcumin-induced unrepaired DNA damage compared to proficient population counterparts. In this report, we show that the protein levels of gadd45α, whose transcript levels are increased during DNA damage and stress signals, are upregulated following curcumin treatment in a dose- and time-dependent manner. We further observed that cells compromised for Mlh1 function (HCT116 + Ch2) displayed ~twofold increased GADD45α upregulation compared to similarly treated proficient counterparts (HCT116 + Ch3). Similarly, suppression of Mlh1 using ShRNA increased GADD45α upregulation upon curcumin treatment. On the other hand, suppression of GADD45α using SiRNA-blocked curcumin-induced cell death induction in Mlh1-deficient cells. Moreover, inhibition of Abl through ST571 treatment and its downstream effector JNK through SP600125 treatment blocked GADD45α upregulation and cell death triggered by curcumin. Collective results lead us to conclude that GADD45α modulates curcumin sensitivity through activation of c-Abl > JNK signaling in a mismatch repair-dependent manner.

Topics: Apoptosis; Base Pair Mismatch; Caspase 3; Caspase 9; Cell Cycle Proteins; Cell Line, Tumor; Colorectal Neoplasms; Curcumin; DNA Repair; Humans; MAP Kinase Kinase 4; Nuclear Proteins; Proto-Oncogene Proteins c-abl

Cell cycle progression and DNA synthesis are essential steps in cancer cell growth and resistance. Thymidylate synthase (TS) is a therapeutic target for 5FU. Curcumin is a potent inhibitor of NF-κB. EF31 and UBS109 are potent synthetic analogues of curcumin. We tested the hypothesis that inhibition of NF-κB translocation by curcumin and its analogs EF31 and UBS109 can inhibit cell cycle progression and downregulate TS levels in colorectal cancer (CRC) cell lines. Two CRC cell lines (HCT116 and HT-29) were either untreated (control) or treated with IC50 concentrations of curcumin, EF31 UBS109 led to G0/G1 cell cycle arrest. Treatment with curcumin, EF31 or UBS109 inhibited NF-κB, downregulated survival pathways and inhibited cell cycle progression. Arrest in the G0/G1 phase was associated with downregulation of the transcription factor E2F-1 and its target gene TS. NF-κB over-expression induced E2F-1 and TS protein and mRNA levels in both cell lines. EF31 and UBS109 treatment significantly decreased tumor growth in compared to untreated tumors. EF31 and UBS109 are promising agents for the prevention and treatment of CRC.

Topics: Animals; Cell Cycle Checkpoints; Cell Line, Tumor; Colorectal Neoplasms; Curcumin; Down-Regulation; Female; Humans; Mice; NF-kappa B; Piperidones; Protein Transport; Pyridines; Thymidylate Synthase

This study investigated the effect of curcumin on colorectal cancer stem cells (CCSCs) and its possible mechanism. Comparison of the metabolic profiles of human adenomatous polyp (N = 61) and colorectal cancer (CRC) (N = 57) tissue found statistically significant differences (p < 0.05) in their composition of adenosine monophosphate (AMP), adenine, 5'-methythioadenosine, 3-hydroxybutyric acid, prostaglandin E2, threonine, and glutamine. Our cell culture model study found that curcumin treatment (50 μM for 48 h) did indeed increase apoptosis of CRC cells as well as of CCSCs, but at a significant level only in CD44(+) cells. Further metabolic profile studies of the CRC, CD44(+), and CD44(-) cells indicated that curcumin treatment increased glyceraldehyde and hydroxypropionic acid in CD44(-) cells but decreased glutamine content in both curcumin-treated CRC and CD44(+) cells. Based on our comparison of the metabolic profiles of human tissues and cancer cells, we suggest that curcumin might couple with CD44 and that curcumin-CD44(+) coupling at the cell membrane might have some blocking effect on the transport of glutamine into the cells, thus decreasing the glutamine content in the CD44(+) cells and inducing apoptosis.

Topics: Apoptosis; Cell Line, Tumor; Colorectal Neoplasms; Curcumin; Glutamine; Humans; Hyaluronan Receptors; Metabolome; Neoplastic Stem Cells

Resistance to oxaliplatin (OXA) is a complex process affecting the outcomes of metastatic colorectal cancer (CRC) patients treated with this drug. De-regulation of the NF-κB signalling pathway has been proposed as an important mechanism involved in this phenomenon. Here, we show that NF-κB was hyperactivated in in vitro models of OXA-acquired resistance but was attenuated by the addition of Curcumin, a non-toxic NF-κB inhibitor. The concomitant combination of Curcumin + OXA was more effective and synergistic in cell lines with acquired resistance to OXA, leading to the reversion of their resistant phenotype, through the inhibition of the NF-κB signalling cascade. Transcriptomic profiling revealed the up-regulation of three NF-κB-regulated CXC-chemokines, CXCL8, CXCL1 and CXCL2, in the resistant cells that were more efficiently down-regulated after OXA + Curcumin treatment as compared to the sensitive cells. Moreover, CXCL8 and CXCL1 gene silencing made resistant cells more sensitive to OXA through the inhibition of the Akt/NF-κB pathway. High expression of CXCL1 in FFPE samples from explant cultures of CRC patients-derived liver metastases was associated with response to OXA + Curcumin. In conclusion, we suggest that combination of OXA + Curcumin could be an effective treatment, for which CXCL1 could be used as a predictive marker, in CRC patients.

Topics: Antineoplastic Agents; Biomarkers, Tumor; Cell Line, Tumor; Chemokines, CXC; Colorectal Neoplasms; Curcumin; Drug Resistance, Neoplasm; Humans; NF-kappa B; Organoplatinum Compounds; Oxaliplatin; Signal Transduction

The B-cell-specific Moloney murine leukemia virus integration site 1 (BMI1) locus encodes a 37-kD protein that is a key regulatory component of the polycomb regulatory complex 1 (PRC1). When overexpressed in various cancer types, the BMI1 protein induces cell growth and promotes tumor growth in vitro and in vivo. Curcumin, a major phytochemical in turmeric (Curcuma longa), inhibits the proliferation and survival of many types of cancer cells, both in vitro and in vivo, and has been reported to reduce BMI1 expression in breast cancer cells. In this study, effects of curcumin and two analogs (bisdemethoxycurcumin and dimethoxycurcumin) on BMI1 expression were evaluated in DLD-1 colorectal cancer cells. Bisdemethoxycurcumin (BDMC) is naturally occurring in turmeric, whereas dimethoxycurcumin (DMC) is a synthetic analog of curcumin. All three compounds reduced cell survival, but only the natural compound downregulated BMI1 protein expression; curcumin significantly reduced BMI1 levels more than bisdemethoxycurcumin and dimethoxycurcumin. In addition, curcumin and BDMC inhibit survival of the DLD-1 colorectal cancer cells by inducing apoptosis, whereas DMC inhibits survival by a mechanism other than apoptosis.

Topics: Adult; Antineoplastic Agents; Apoptosis; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Cell Survival; Colorectal Neoplasms; Curcumin; Diarylheptanoids; Down-Regulation; Humans; Male; Polycomb Repressive Complex 1

Colorectal cancer is the most commonly diagnosed malignancy with high mortality rates worldwide. Improved therapeutic strategies with minimal adverse side effects are urgently needed. In this study, the anti-tumor effects of EF24, a novel analog of the natural compound curcumin, were evaluated in colorectal cancer cells.. The anti-tumor activity of EF24 on human colon cancer lines (HCT-116, SW-620, and HT-29) was determined by measures of cell cycle arrest, apoptosis, and mitochondrial function. The contribution of ROS in the EF24-induced anti-tumor activity was evaluated by measures of H. The findings indicated that EF24 treatment dose-dependently inhibited cell viability and caused cell cycle arrest at G2/M phase in all the tested colon cancer cell lines. Furthermore, we demonstrated that EF24 treatment induced apoptosis effectively via enhancing intracellular accumulation of ROS in both HCT-116 and SW-620 cells, but with moderate effects in HT-29 cells. We found that EF24 treatment decreased the mitochondrial membrane potential in the colon cancer cells, leading to the release of mitochondrial cytochrome c. Also, EF24 induced activation of caspases 9 and 3, causing decreased Bcl-2 protein expression and Bcl-2/Bax ratio. Pretreatment with NAC, a ROS scavenger, abrogated the EF24-induced cell death, apoptosis, cell cycle arrest, and mitochondrial dysfunction, suggesting an upstream ROS generation which was responsible for the anticancer effects of EF24.. Our findings support an anticancer mechanism by which EF24 enhanced ROS accumulation in colon cancer cells, thereby resulting in mitochondrial membrane collapse and activated intrinsic apoptotic signaling. Thus, EF24 could be a potential candidate for therapeutic application of colon cancer.

Topics: Antineoplastic Agents; Apoptosis; Benzylidene Compounds; Caspases; Cell Line, Tumor; Cell Survival; Colorectal Neoplasms; Curcumin; Cytochromes c; Humans; Membrane Potential, Mitochondrial; Mitochondria; Piperidones; Reactive Oxygen Species

Curcumin, the major pigment of the dietary spice turmeric, has the potential for chemoprevention by promotion of apoptosis. Here, we investigated the molecular mechanisms of curcumin in glycolytic inhibition and apoptotic induction in human colorectal cancer HCT116 and HT29 cells. On the one hand, curcumin downregulated the expression and activity of hexokinase II (HKII) in HCT116 and HT29 cells in a concentration-dependent manner, but had little effect on the other key glycolytic enzymes (PFK, PGM, and LDH). On the other, curcumin induced dissociation of HKII from the mitochondria, resulting in mitochondrial-mediated apoptosis. Furthermore, the phosphorylation of mitochondrial HKII through AKT was responsible for the curcumin-induced dissociation of HKII, which was different from the mechanism of HKII inhibitor 3-BrPA. These results have important implications for the metabolism reprogramming effect and the susceptibility to curcumin-induced mitochondrial cytotoxicity through the regulation of HKII, and provide a molecular basis for the development of naturally compounds as novel anticancer agents for colorectal carcinoma.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Curcumin; Glycolysis; HCT116 Cells; Hexokinase; HT29 Cells; Humans; Mitochondria; Phosphorylation; Proto-Oncogene Proteins c-akt

Studies have shown chemopreventive and/or chemotherapeutic effects of several curcumin-based combinatorial treatments on colorectal cancer cells. However, their in vivo effects remain unclear. This study has demonstrated the therapeutic effect of curcumin and oxaliplatin, alone or in combination, on subcutaneously xenografted LoVo human colorectal cancer cells in immunodeficient (nu/nu) mice in vivo. Combinatorial administration of curcumin and oxaliplatin evidently inhibited the growth of colorectal cancer in nude mice, which was significantly more effective than either agent alone. Curcumin combined with oxaliplatin treatment induced apoptosis, accompanied by ultrastructural changes and cell cycle arrest in S and G2/M phases. Further mechanism analysis indicated that while the number of apoptotic tumor cells and the expression of Bax, caspase-3, and poly (ADP-ribose) polymerase (PARP) increased significantly, the expression of Bcl-2, survivin, HSP70, pro-caspase-3, and pro-PARP were dramatically suppressed in tumor cells after the treatment with combinatorial curcumin and oxaliplatin for 22 days. Taken together, the present study has demonstrated that administration of combined curcumin and oxaliplatin effectively suppressed colorectal carcinoma in vivo through inducing apoptosis and thus may provide an effective treatment for colorectal carcinoma.

Topics: Animals; Apoptosis; Apoptosis Regulatory Proteins; Cell Cycle Checkpoints; Cell Line, Tumor; Colorectal Neoplasms; Curcumin; Drug Synergism; Drug Therapy, Combination; Humans; Male; Mice; Mice, Nude; Organoplatinum Compounds; Oxaliplatin; Xenograft Model Antitumor Assays

Resistance to cytotoxic chemotherapy is a major cause of mortality in colorectal cancer (CRC) patients. Chemoresistance has been linked primarily to a subset of cancer cells undergoing epithelial-mesenchymal transition (EMT). Curcumin, a botanical with antitumorigenic properties, has been shown to enhance sensitivity of cancer cells to chemotherapeutic drugs, but the molecular mechanisms underlying this phenomenon remain unclear. Effects of curcumin and 5-fluorouracil (5FU) individually, and in combination, were examined in parental and 5FU resistant (5FUR) cell lines. We performed a series of growth proliferation and apoptosis assays in 2D and 3D cell cultures. Furthermore, we identified and analyzed the expression pattern of a subset of putative EMT-suppressive microRNAs (miRNAs) and their downstream target genes regulated by curcumin. Chemosensitizing effects of curcumin were validated in a xenograft mouse model. Combined treatment with curcumin and 5FU enhanced cellular apoptosis and inhibited proliferation in both parental and 5FUR cells, whereas 5FU alone was ineffective in 5FUR cells. A group of EMT-suppressive miRNAs were upregulated by curcumin treatment in 5FUR cells. Curcumin suppressed EMT in 5FUR cells by downregulating BMI1, SUZ12 and EZH2 transcripts, key mediators of cancer stemness-related polycomb repressive complex subunits. Using a xenograft and mathematical models, we further demonstrated that curcumin sensitized 5FU to suppress tumor growth. We provide novel mechanistic evidence for curcumin-mediated sensitization to 5FU-related chemoresistance through suppression of EMT in 5FUR cells via upregulation of EMT-suppressive miRNAs. This study highlights the potential therapeutic usefulness of curcumin as an adjunct in patients with chemoresistant advanced CRC.

Topics: Animals; Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Colorectal Neoplasms; Curcumin; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Fluorouracil; Gene Expression Regulation, Neoplastic; Humans; Male; Mice, Nude; MicroRNAs; Xenograft Model Antitumor Assays

Colorectal cancer is one of the most common causes of cancer-associated mortality worldwide, but it is truly a preventable disease. Both curcumin and boswellic acids are well-established dietary botanicals with potent antitumorigenic properties that have been shown to modulate multiple oncogenic pathways. Recent data suggest that the chemopreventive effects of these botanicals may, in part, be mediated through regulation of key cancer-related microRNAs (miRNA) and their downstream gene targets. Here, we investigated the antitumorigenic effects of curcumin and 3 acetyl-11-keto-β-boswellic acid (AKBA) on modulation of specific cancer-related miRNAs in colorectal cancer cells and validated their protective effects in vivo using a xenograft mouse model. Both curcumin and AKBA inhibited cellular proliferation, induced apoptosis and cell-cycle arrest in colorectal cancer cell lines, and these effects were significantly enhanced with combined treatment. Gene-expression arrays revealed that curcumin and AKBA regulated distinct cancer signaling pathways, including key cell-cycle regulatory genes. Combined bioinformatics and in silico analysis identified apoptosis, proliferation, and cell-cycle regulatory signaling pathways as key modulators of curcumin and AKBA-induced anticancer effects. We discovered that curcumin and AKBA induced upregulation of tumor-suppressive miR-34a and downregulation of miR-27a in colorectal cancer cells. Furthermore, we demonstrated in a mouse xenograft model that both curcumin and AKBA treatments suppressed tumor growth, which corresponded with alterations in the expression of miR-34a and miR-27a, consistent with our in vitro findings. Herein, we provide novel mechanistic evidence for the chemopreventive effects of curcumin and AKBA through regulation of specific miRNAs in colorectal cancer.

Topics: Adenocarcinoma; Animals; Caco-2 Cells; Cell Line, Tumor; Chemoprevention; Colorectal Neoplasms; Curcumin; Gene Expression Regulation, Neoplastic; HCT116 Cells; HT29 Cells; Humans; Male; Mice; Mice, Nude; MicroRNAs; Triterpenes; Xenograft Model Antitumor Assays

To overcome the limitations of animal-based experiments, 3D culture models mimicking the tumor microenvironment in vivo are gaining attention. Herein, we investigated an alginate-based 3D scaffold for screening of 5-fluorouracil (5-FU) or/and curcumin on malignancy of colorectal cancer cells (CRC).. The potentiation effects of curcumin on 5-FU against proliferation and metastasis of HCT116 cell and its corresponding isogenic 5-FU-chemoresistant cells (HCT116R) were examined in a 3D-alginate tumor model.. CRC cells encapsulated in alginate were able to proliferate in 3D-colonospheres in a vivo-like phenotype and invaded from alginate. During cultivation of cells in alginate, we could isolate 3 stages of cells, (1) alginate proliferating (2) invasive and (3) adherent cells. Tumor-promoting factors (CXCR4, MMP-9, NF-κB) were significantly increased in the proliferating and invasive compared to the adherent cells, however HCT116R cells overexpressed factors in comparison to the parental HCT116, suggesting an increase in malignancy behavior. In alginate, curcumin potentiated 5-FU-induced decreased capacity for proliferation, invasion and increased more sensitivity to 5-FU of HCT116R compared to the HCT116 cells. IC50 for HCT116 to 5-FU was 8nM, but co-treatment with 5 μM curcumin significantly reduced 5-FU concentrations in HCT116 and HCT116R cells (0.8nM, 0.1nM, respectively) and these effects were accompanied by down-regulation of NF-κB activation and NF-κB-regulated gene products.. Our results demonstrate that the alginate provides an excellent tumor microenvironment and indicate that curcumin potentiates and chemosensitizes HCT116R cells to 5-FU-based chemotherapy that may be useful for the treatment of CRC and to overcome drug resistance.

Topics: Alginates; Animals; Apoptosis; Cell Proliferation; Colorectal Neoplasms; Curcumin; Drug Synergism; Fluorouracil; Glucuronic Acid; HCT116 Cells; Hexuronic Acids; Humans; Matrix Metalloproteinase 9; Mice; Neoplasm Invasiveness; Receptors, CXCR4; Signal Transduction; Tumor Microenvironment; Xenograft Model Antitumor Assays

To explore the chemopreventive effect of curcumin on DMH induced colorectal carcinogenesis and the underlining mechanism.. Totally 40 Wistar rats were divided into the model group and the curcumin group by random digit table, 20 in each group. Meanwhile, a normal control group was set up (n =10). A colorectal cancer model was induced by subcutaneously injecting 20 mg/kg DMH. The tumor incidence and the inhibition rate were calculated. The effect of curcumin on the expression of peroxisome proliferator-activated receptor gamma (PPARγ) in rat colon mucosal tissues was observed using immunohistochemistry and Western blot. HT 29 cell line were cultured and divided into a control group, the curcumin + GW9662 (2-chloro-5-nitro-N-4-phenylbenzamide) intervention group, and the curcumin group. The inhibition of different concentrations curcumin on HT29 cell line was detected using MTT. The expression of curcumin on PPARy was also detected using Western blot.. The tumor incidence was 80. 00% (12/15 cases) in the model group, obviously higher than that of the curcumin group (58. 82%, 10/17 cases, P <0. 05). The inhibition rate of curcumin on DMH induced colorected carcinoma reached 26. 46%. Compared with the normal control group, the expression of PPARγ protein was significantly increased in the curcumin group and the model group (P <0. 01). Compared with the model group at the same time point, the expression of PPARy protein was significantly enhanced in the curcumin group (P <0. 05). MTT analysis showed that curcumin could inhibit the proliferation of in vitro HT 29 cells in dose and time dependent manners. The expression of PPARy protein was significantly increased in the GW9662 group and the curcumin group, showing statistical difference when compared with the normal control group (P <0. 01). Compared with the GW9662 group, the expression of PPARγ protein was significantly increased in the curcumin group (P <0. 01).. Curcumin could inhibit DMH-induced rat colorectal carcinogenesis and the growth of in vitro cultured HT 29 cell line, which might be achieved by activating PPARy signal transduction pathway.

Topics: Anilides; Animals; Carcinogenesis; Colorectal Neoplasms; Curcumin; PPAR gamma; Rats; Rats, Wistar; Signal Transduction

The purpose of the present study was to fabricate polymeric nanoparticles as drug carriers for encapsulated curcumin with enhanced anti-colorectal cancer applications. Nanoparticles were formulated from chitosan and gum arabic, natural polysaccharides, via an emulsification solvent diffusion method. The formation of curcumin nanoparticles was confirmed by Fourier transform infrared spectroscopy and differential scanning calorimeter. The results show that curcumin was entrapped in carriers with +48 mV, 136 nm size, and high encapsulation efficiency (95%). Based on an in vitro release study, we inferred that curcumin nanoparticles could tolerate hydrolysis due to gastric juice or small intestinal enzymes, and therefore, it should reach the colon largely intact. In addition, curcumin nanoparticles had higher anti-colorectal cancer properties than free curcumin due to greater cellular uptake. Therefore, we concluded that curcumin was successfully encapsulated in chitosan-gum arabic nanoparticles with superior anti-colorectal cancer activity.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Chitosan; Colon; Colorectal Neoplasms; Curcumin; Drug Carriers; Gum Arabic; Humans; Hydrolysis; Nanoparticles; Rectum

Intestinal microbiota influences the progression of colitis-associated colorectal cancer. With diet being a key determinant of the gut microbial ecology, dietary interventions are an attractive avenue for the prevention of colitis-associated colorectal cancer. Curcumin is the most active constituent of the ground rhizome of the Curcuma longa plant, which has been demonstrated to have anti-inflammatory, antioxidative, and antiproliferative properties.. Il10 mice on 129/SvEv background were used as a model of colitis-associated colorectal cancer. Starting at 10 weeks of age, wild-type or Il10 mice received 6 weekly intraperitoneal injections of azoxymethane (AOM) or phosphate-buffered saline (PBS) and were started on either a control or a curcumin-supplemented diet. Stools were collected every 4 weeks for microbial community analysis. Mice were killed at 30 weeks of age.. Curcumin-supplemented diet increased survival, decreased colon weight/length ratio, and, at 0.5%, entirely eliminated tumor burden. Although colonic histology indicated improvement with curcumin, no effects of mucosal immune responses have been observed in PBS/Il10 mice and limited effects were seen in AOM/Il10 mice. In wild-type and in Il10 mice, curcumin increased bacterial richness, prevented age-related decrease in alpha diversity, increased the relative abundance of Lactobacillales, and decreased Coriobacterales order. Taxonomic profile of AOM/Il10 mice receiving curcumin was more similar to those of wild-type mice than those fed control diet.. In AOM/Il10 model, curcumin reduced or eliminated colonic tumor burden with limited effects on mucosal immune responses. The beneficial effect of curcumin on tumorigenesis was associated with the maintenance of a more diverse colonic microbial ecology.

Topics: Animals; Azoxymethane; Carcinogens; Cell Transformation, Neoplastic; Colitis; Colon; Colorectal Neoplasms; Curcumin; Dietary Supplements; Disease Models, Animal; Immunity, Mucosal; Intestinal Mucosa; Mice; Mice, 129 Strain; Mice, Knockout; Microbiota

In this work, we prepared an in situ gel-forming composite drug delivery system (DDS) to treat colorectal peritoneal carcinomatosis. The composite DDS was based on curcumin loaded polymeric micelles (Cur-M) and thermosensitive hydrogel. Cur-M had a particle size of 27.1 ± 1.3 nm with polydisperse index of 0.149 ± 0.017, and the drug loading and encapsulation efficiency of Cur-M were 14.82 ± 0.07 and 98.83 ± 0.45%, respectively. The prepared Cur-M in thermosensitive hydrogel system (Cur-H) was a free-flowing sol at ambient temperature, and converted into non-flowing gel at body temperature, serving as a drug depot. In vitro drug release behavior suggested that Cur-H and Cur-M could release Cur in an extent period, and Cur-H showed a slower cumulative release rate. In addition, compared with free Cur, Cur-M showed higher cytotoxicity and apoptotic induction efficiency. Furthermore, colorectal peritoneal carcinomatosis mouse model was used to evaluate the anti-tumor activity of Cur-H, and the results suggested that Cur-H could inhibit tumor growth and metastasis, and prolonged survival of tumor-bearing mice. Immunohistochemical and immunofluorescent staining of tumor tissues in each group were conducted. The results demonstrated that tumors in Cur-H group showed lower proliferation activity, more apoptotic cells, and fewer microvessels. Besides, pharmacokinetic studies of Cur-H and Cur-M by intraperitoneal administration were performed. Compared with Cur-M, Cur-H showed a higher AUC and longer t½. Thus, the above results suggested that Cur-H may have potential applications in colorectal peritoneal carcinomatosis.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Colorectal Neoplasms; Curcumin; Delayed-Action Preparations; Diffusion; Drug Synergism; Hydrogels; Mice; Mice, Inbred BALB C; Micelles; Nanocapsules; Particle Size; Temperature; Treatment Outcome

While targeted agents are an important part of the treatment arsenal for colorectal cancer, there is still a lack of efficient small-molecule targeted agents based on the understanding of pathogenic molecular mechanisms. In this study, curcumin analog RL71 displayed potent cytotoxicity towards human colon cancer cells with an IC50 of 0.8 µM in SW480 cells and inhibited xenotransplanted tumor growth in a dose-dependent manner. Using affinity chromatography, we identified sarco/endoplasmic reticulum calcium-ATPase (SERCA) 2 as the binding target of RL71. Most notably, RL71 demonstrated special binding to SERCA2 at a novel site with the lowest estimated free energy -8.89 kcal mol(-1), and the SERCA2 residues critical for RL71 binding were identified. RL71 suppressed the Ca(2+)-ATPase activity of SERCA2 both in vitro and in vivo, accompanied by the induction of endoplasmic reticulum stress leading to apoptosis and G2/M cycle arrest in SW480 cells. In addition, RL71 showed synergistic cytotoxicity with the pan-SERCA inhibitor thapsigargin. These results suggest that RL71 could be a selective small-molecule inhibitor of SERCA2, and that it may serve as a lead compound for the study of targeted colorectal cancer therapy.

Topics: Animals; Antineoplastic Agents; Apoptosis; Blotting, Western; Calcium; Cell Cycle; Cell Proliferation; Colorectal Neoplasms; Curcumin; Diarylheptanoids; Endoplasmic Reticulum Stress; Female; Gene Expression Regulation, Neoplastic; Humans; Immunoenzyme Techniques; Mice; Mice, Nude; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Curcumin, a polyphenol isolated from the plant Curcuma longa, displays chemotherapeutic and chemopreventive effects in diverse cancers, including colorectal cancer. A mono-carbonyl analogue B63 was synthesized through several chemical modifications of the basic structure of curcumin to increase its biological activity and bioavailability. In vitro assays showed potent anti-proliferative effects of B63 on colon cancer cells (about 2 fold more effective than curcumin based on IC50). B63 treatment also induced significant necrosis, apoptosis, and S phase cell cycle arrest in SW620 colon cancer cells. The pro-apoptotic proteins Bad and Bim were up-regulated, and cytochrome c release from the mitochondria into the cytosol was enhanced, resulting in pro-caspase-3 and PARP-1 cleavage. Furthermore, the anticancer activity of B63 was dependent on intracellular ROS from damaged mitochondrial function and induced endoplasmic reticulum (ER) stress. In vivo, 50 mg/kg of B63 inhibit tumor growth similarly to 100 mg/kg curcumin in a mouse xenograft model using SW620 cells. These results suggest that the curcumin derivative B63 has a greater anticancer capacity than the parent curcumin in colon cancer cells and that the necrotic and apoptotic effects of B63 are mediated by ROS resulting from ER stress and mitochondrial dysfunction.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Proliferation; Colorectal Neoplasms; Curcumin; Dose-Response Relationship, Drug; Endoplasmic Reticulum Stress; Female; HCT116 Cells; Humans; Inhibitory Concentration 50; Mice, Inbred BALB C; Mice, Nude; Mitochondria; Necrosis; Oxidative Stress; Phytotherapy; Plants, Medicinal; Reactive Oxygen Species; S Phase Cell Cycle Checkpoints; Time Factors; Tumor Burden; Xenograft Model Antitumor Assays

We wish to implement a proteomics-based approach to pick and identify the proteins associated with curcumin enhancing efficacy of irinotecan inducing apoptosis of colorectal cancer LOVO cells, and further explore their synergy mechanism by bioinformatics.. A colorectal cancer cell line (LOVO cell) treated by curcumin combined with irinotecan in different ways respectively was used as our comparative model. Protein spots were analyzed through MALDI-TOF/TOF. The location and function of differential protein spots were analyzed through UniProt database. Protein-protein interactions were examined through String software.. A total of 54 protein spots differentially expressed with 1.5-fold difference were picked, 11 of which were repeated. They mainly were involved in intracellular calcium pathways, cellular respiratory chain pathway and intracellular redox reaction pathways of LOVO cell. According to the function of various protein points, combining with varying curves of protein points in each treatment groups, we selected five interesting protein spots, 4 of which exists Protein-protein interactions, and they were close to the formation and reduction of disulfides in intracellular endoplasmic reticulum (ER).. We selected preliminary but comprehensive data about differential expression protein spots of LOVO cell. Among these, the five interesting differential expression protein spots identified in this study may provide new insight into LOVO cell therapeutic biomarkers. Curcumin may suppress GSTM5 expression to enhance the lethal effect of irinotecan on LOVO cells, and maybe their combination via the affection of PDI and PRDX4 to disturb the formation and reduction of disulfides results in inducing apoptosis of LOVO cell.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Camptothecin; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Curcumin; Humans; Irinotecan; Proteomics; Signal Transduction; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

Cortactin (CTTN), first identified as a major substrate of the Src tyrosine kinase, actively participates in branching F-actin assembly and in cell motility and invasion. CTTN gene is amplified and its protein is overexpressed in several types of cancer. The phosphorylated form of cortactin (pTyr(421)) is required for cancer cell motility and invasion. In this study, we demonstrate that a majority of the tested primary colorectal tumor specimens show greatly enhanced expression of pTyr(421)-CTTN, but no change at the mRNA level as compared to healthy subjects, thus suggesting post-translational activation rather than gene amplification in these tumors. Curcumin (diferulolylmethane), a natural compound with promising chemopreventive and chemosensitizing effects, reduced the indirect association of cortactin with the plasma membrane protein fraction in colon adenocarcinoma cells as measured by surface biotinylation, mass spectrometry, and Western blotting. Curcumin significantly decreased the pTyr(421)-CTTN in HCT116 cells and SW480 cells, but was ineffective in HT-29 cells. Curcumin physically interacted with PTPN1 tyrosine phosphatases to increase its activity and lead to dephosphorylation of pTyr(421)-CTTN. PTPN1 inhibition eliminated the effects of curcumin on pTyr(421)-CTTN. Transduction with adenovirally-encoded CTTN increased migration of HCT116, SW480, and HT-29. Curcumin decreased migration of HCT116 and SW480 cells which highly express PTPN1, but not of HT-29 cells with significantly reduced endogenous expression of PTPN1. Curcumin significantly reduced the physical interaction of CTTN and pTyr(421)-CTTN with p120 catenin (CTNND1). Collectively, these data suggest that curcumin is an activator of PTPN1 and can reduce cell motility in colon cancer via dephosphorylation of pTyr(421)-CTTN which could be exploited for novel therapeutic approaches in colon cancer therapy based on tumor pTyr(421)-CTTN expression.

Topics: Adenocarcinoma; Antineoplastic Agents; Blotting, Western; Catenins; Cell Line, Tumor; Cell Membrane; Cell Movement; Colorectal Neoplasms; Cortactin; Curcumin; Delta Catenin; Gene Expression Regulation, Neoplastic; HCT116 Cells; HT29 Cells; Humans; Immunohistochemistry; Microscopy, Confocal; Phosphorylation; Protein Binding; Protein Processing, Post-Translational; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Reverse Transcriptase Polymerase Chain Reaction; Tyrosine

To improve the efficacy of drug delivery, active targeted nanotechnology-based drug delivery systems are gaining considerable attention as they have the potential to reduce side effects, minimize toxicity, and improve efficacy of anticancer treatment. In this work CUR-NPs (curcumin-loaded lipid-polymer-lecithin hybrid nanoparticles) were synthesized and functionalized with ribonucleic acid (RNA) Aptamers (Apts) against epithelial cell adhesion molecule (EpCAM) for targeted delivery to colorectal adenocarcinoma cells. These CUR-encapsulated bioconjugates (Apt-CUR-NPs) were characterized for particle size, zeta potential, drug encapsulation, stability, and release. The in vitro specific cell binding, cellular uptake, and cytotoxicity of Apt-CUR-NPs were also studied. The Apt-CUR-NP bioconjugates exhibited increased binding to HT29 colon cancer cells and enhancement in cellular uptake when compared to CUR-NPs functionalized with a control Apt (P<0.01). Furthermore, a substantial improvement in cytotoxicity was achieved toward HT29 cells with Apt-CUR-NP bioconjugates. The encapsulation of CUR in Apt-CUR-NPs resulted in the increased bioavailability of delivered CUR over a period of 24 hours compared to that of free CUR in vivo. These results show that the EpCAM Apt-functionalized CUR-NPs enhance the targeting and drug delivery of CUR to colorectal cancer cells. Further development of CUR-encapsulated, nanosized carriers will lead to improved targeted delivery of novel chemotherapeutic agents to colorectal cancer cells.

Topics: Adenocarcinoma; Animals; Antigens, Neoplasm; Antineoplastic Agents; Aptamers, Nucleotide; Cell Adhesion Molecules; Cell Survival; Colorectal Neoplasms; Curcumin; Drug Carriers; Drug Delivery Systems; Drug Stability; Epithelial Cell Adhesion Molecule; HEK293 Cells; HT29 Cells; Humans; Lactic Acid; Lecithins; Male; Nanoconjugates; Nanomedicine; Nanoparticles; Nanotechnology; Polyethylene Glycols; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Rats; Rats, Sprague-Dawley

The poor water solubility and bioactivity of lipophilic phytochemicals can be potentially improved by delivery systems. In this study, a low-cost, low-energy, and organic solvent-free encapsulation technology was studied by utilizing the pH-dependent solubility properties of curcumin and self-assembly properties of sodium caseinate (NaCas). Curcumin was deprotonated and dissolved, while NaCas was dissociated at pH 12 and 21 °C for 30 min. The subsequent neutralization enabled the encapsulation of curcumin in self-assembled casein nanoparticles. The degradation of curcumin under encapsulation conditions was negligible based on visible light and nuclear magnetic resonance spectroscopy. The dissociation of NaCas at pH 12 and reassociation after neutralization were confirmed using dynamic light scattering and analytical ultracentrifugation. The curcumin encapsulated in casein nanoparticles showed significantly improved anti-proliferation activity against human colorectal and pancreatic cancer cells. The studied encapsulation method is promising to utilize lipophilic compounds in food or pharmaceutical industries.

Topics: Antioxidants; Caseins; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Curcumin; Drug Carriers; Food Technology; Free Radical Scavengers; HCT116 Cells; Humans; Hydrogen-Ion Concentration; Light; Magnetic Resonance Spectroscopy; Micelles; Microscopy, Electron, Transmission; Nanoparticles; Nanotechnology; Pancreatic Neoplasms; Scattering, Radiation; Solubility; Spectrometry, Fluorescence; Temperature; Water

Prostaglandin E2 (PGE2) promotes tumor-persistent inflammation, frequently resulting in cancer. Curcumin is a diphenolic turmeric that inhibits carcinogenesis and induces apoptosis. PGE2 inhibits curcumin-induced apoptosis; however, the underlying inhibitory mechanisms in colon cancer cells remain unknown. The aim of the present study is to investigate the survival role of PGE2 and whether addition of exogenous PGE2 affects curcumin-induced cell death. HCT-15 cells were treated with curcumin and PGE2, and protein expression levels were investigated via Western blot. Reactive oxygen species (ROS) generation, lipid peroxidation, and intracellular glutathione (GSH) levels were confirmed using specific dyes. The nuclear factor-kappa B (NF-κB) DNA-binding was measured by electrophoretic mobility shift assay (EMSA). PGE2 inhibited curcumin-induced apoptosis by suppressing oxidative stress and degradation of PARP and lamin B. However, exposure of cells to the EP2 receptor antagonist, AH6809, and the PKA inhibitor, H89, before treatment with PGE2 or curcumin abolished the protective effect of PGE2 and enhanced curcumin-induced cell death. PGE2 activates PKA, which is required for cAMP-mediated transcriptional activation of CREB. PGE2 also activated the Ras/Raf/Erk pathway, and pretreatment with PD98059 abolished the protective effect of PGE2. Furthermore, curcumin treatment greatly reduced phosphorylation of CREB, followed by a concomitant reduction of NF-κB (p50 and p65) subunit activation. PGE2 markedly activated nuclear translocation of NF-κB. EMSA confirmed the DNA-binding activities of NF-κB subunits. These results suggest that inhibition of curcumin-induced apoptosis by PGE2 through activation of PKA, Ras, and NF-κB signaling pathways may provide a molecular basis for the reversal of curcumin-induced colon carcinoma cell death.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Colorectal Neoplasms; Curcumin; Dinoprostone; Gene Expression Regulation, Neoplastic; Glutathione; Humans; Lipid Peroxidation; Reactive Oxygen Species; Signal Transduction

Sarco/endoplasmic reticulum calcium ATPase (SERCA) enzymes play important roles in several signal transduction pathways that control proliferation, differentiation and apoptosis. Here, we reported that SERCA2 expression was positively correlated with tumor node metastasis (TNM) stages (n=75, P=0.0251) and grades (n=63, P=0.0146) of patients with colorectal cancer. The animal experiments demonstrated that SERCA2 expression was consistent with PCNA staining of intestinal tissues of male C57BL/6J-Apc(Min/)JNju mice. Besides, SERCA2 expression was also increased in undifferentiated HT-29 cells as compared with that in differentiated HT-29gal cells. Moreover, SERCA2 overexpression promoted proliferation and migration of SW480 cells via activating MAPK and AKT signaling pathways, while silence of SERCA2 inhibited the proliferation and migration of SW480 cells. In addition, we identified that a curcumin analog, F36, exhibited more potent inhibitory effect in colorectal cancer cells than curcumin through inhibiting SERCA2 expression. Taken together, our findings indicate that SERCA2 is involved in the malignant progress of colorectal cancer and maybe a therapeutic target for colorectal cancer treatment. Curcumin analog F36 shows enhanced anti-cancer activity in colorectal cancer cells by targeting SERCA2.

Topics: Animals; Colorectal Neoplasms; Curcumin; HT29 Cells; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Sarcoplasmic Reticulum Calcium-Transporting ATPases

Development of treatment resistance and adverse toxicity associated with classical chemotherapeutic agents highlights the need for safer and effective therapeutic approaches. Herein, we examined the effectiveness of a combination treatment regimen of 5-fluorouracil (5-FU) and curcumin in colorectal cancer (CRC) cells.. Wild type HCT116 cells and HCT116+ch3 cells (complemented with chromosome 3) were treated with curcumin and 5-FU in a time- and dose-dependent manner and evaluated by cell proliferation assays, DAPI staining, transmission electron microscopy, cell cycle analysis and immunoblotting for key signaling proteins.. The individual IC50 of curcumin and 5-FU were approximately 20 µM and 5 µM in HCT116 cells and 5 µM and 1 µM in HCT116+ch3 cells, respectively (p<0.05). Pretreatment with curcumin significantly reduced survival in both cells; HCT116+ch3 cells were considerably more sensitive to treatment with curcumin and/or 5-FU than wild-type HCT116 cells. The IC50 values for combination treatment were approximately 5 µM and 1 µM in HCT116 and 5 µM and 0.1 µM in HCT116+ch3, respectively (p<0.05). Curcumin induced apoptosis in both cells by inducing mitochondrial degeneration and cytochrome c release. Cell cycle analysis revealed that the anti-proliferative effect of curcumin and/or 5-FU was preceded by accumulation of CRC cells in the S cell cycle phase and induction of apoptosis. Curcumin potentiated 5-FU-induced expression or cleavage of pro-apoptotic proteins (caspase-8, -9, -3, PARP and Bax), and down-regulated anti-apoptotic (Bcl-xL) and proliferative (cyclin D1) proteins. Although 5-FU activated NF-κB/PI-3K/Src pathway in CRC cells, this was down-regulated by curcumin treatment through inhibition of IκBα kinase activation and IκBα phosphorylation.. Combining curcumin with conventional chemotherapeutic agents such as 5-FU could provide more effective treatment strategies against chemoresistant colon cancer cells. The mechanisms involved may be mediated via NF-κB/PI-3K/Src pathways and NF-κB regulated gene products.

Topics: Antineoplastic Agents; Apoptosis; Blotting, Western; Cell Line, Tumor; Colorectal Neoplasms; Curcumin; Drug Synergism; Fluorouracil; Humans; Microscopy, Electron, Transmission; NF-kappa B; Signal Transduction; src-Family Kinases

Recent evidence suggests that several dietary polyphenols may exert their chemopreventive effect through epigenetic modifications. Curcumin is one of the most widely studied dietary chemopreventive agents for colon cancer prevention, however, its effects on epigenetic alterations, particularly DNA methylation, remain unclear. Using systematic genome-wide approaches, we aimed to elucidate the effect of curcumin on DNA methylation alterations in colorectal cancer cells.. To evaluate the effect of curcumin on DNA methylation, three CRC cell lines, HCT116, HT29 and RKO, were treated with curcumin. 5-aza-2'-deoxycytidine (5-aza-CdR) and trichostatin A treated cells were used as positive and negative controls for DNA methylation changes, respectively. Methylation status of LINE-1 repeat elements, DNA promoter methylation microarrays and gene expression arrays were used to assess global methylation and gene expression changes. Validation was performed using independent microarrays, quantitative bisulfite pyrosequencing, and qPCR.. As expected, genome-wide methylation microarrays revealed significant DNA hypomethylation in 5-aza-CdR-treated cells (mean β-values of 0.12), however, non-significant changes in mean β-values were observed in curcumin-treated cells. In comparison to mock-treated cells, curcumin-induced DNA methylation alterations occurred in a time-dependent manner. In contrast to the generalized, non-specific global hypomethylation observed with 5-aza-CdR, curcumin treatment resulted in methylation changes at selected, partially-methylated loci, instead of fully-methylated CpG sites. DNA methylation alterations were supported by corresponding changes in gene expression at both up- and down-regulated genes in various CRC cell lines.. Our data provide previously unrecognized evidence for curcumin-mediated DNA methylation alterations as a potential mechanism of colon cancer chemoprevention. In contrast to non-specific global hypomethylation induced by 5-aza-CdR, curcumin-induced methylation changes occurred only in a subset of partially-methylated genes, which provides additional mechanistic insights into the potent chemopreventive effect of this dietary nutraceutical.

Topics: Cell Line, Tumor; Cell Proliferation; Cell Survival; Colorectal Neoplasms; CpG Islands; Curcumin; DNA Methylation; Gene Expression Regulation, Neoplastic; Genes, Neoplasm; Genetic Loci; Humans; Long Interspersed Nucleotide Elements; Reproducibility of Results; Time Factors

Curcumin (diferuloylmethane), the yellow pigment of turmeric, is one of the most commonly used and extensively studied phytochemicals due to its pleiotropic effects in several human cancers. In the current study, the therapeutic efficacy of curcumin was investigated in human colorectal carcinoma HCT-15 cells. Curcumin inhibited HCT-15 cells proliferation and induced apoptosis in a dose- and time-dependent manner. Hoechst 33342 and DCFHDA staining revealed morphological and biochemical features of apoptosis as well as ROS generation in HCT-15 cells treated with 30 and 50 μM curcumin. Over-expression of pre-mRNA processing factor 4B (Prp4B) and p53 mutations have been reported as hallmarks of cancer cells. Western blot analysis revealed that curcumin treatment activated caspase-3 and decreased expression of p53 and Prp4B in a time-dependent manner. Transfection of HCT-15 cells with Prp4B clone perturbed the growth inhibition induced by 30 μM curcumin. Fractionation of cells revealed increased accumulation of Prp4B in the nucleus, following its translocation from the cytoplasm. To further evaluate the underlying mechanism and survival effect of Prp4B, we generated siRNA-Prp4B HCT15 clones. Knockdown of Prp4B with siRNA diminished the protective effects of Prp4B against curcumin-induced apoptosis. These results suggest a possible underlying molecular mechanism in which Prp4B over-expression and activity are closely associated with the survival and regulation of apoptotic events in human colon cancer HCT-15 cells.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Caspase 3; Cell Growth Processes; Cell Line, Tumor; Colorectal Neoplasms; Curcumin; Gene Expression Regulation, Neoplastic; Humans; Mutation; Protein Serine-Threonine Kinases; Reactive Oxygen Species; Ribonucleoprotein, U4-U6 Small Nuclear; RNA, Small Interfering; Transgenes; Tumor Suppressor Protein p53

Topoisomerases-IIα (TOP2A) enzyme is essential for cell viability due to its fundamental role in DNA metabolism and in chromatin organization during interphase and mitosis. TOP2A expression is finely regulated at the transcriptional level through the binding of the CCAAT-transcription factor NF-Y to its promoter. Overexpression and/or amplification of TOP2A have been observed in many types of cancers. For this reason, TOP2A is the target of the most widely successful drugs in cancer chemotherapy, such as TOP2A poisons, which stabilize TOP2A-DNA cleavage complexes and create DSBs, leading to chromosome damage and cell death. We previously reported that the Curcumin-derivative bis-DemethoxyCurcumin (bDMC) is an anti-proliferative agent that inhibits cell growth by concomitant G1/S and G2/M arrest. Here we showed that bDMC irreversibly induces DSBs in cancer cells, but not in normal cells, by targeting TOP2A activity and expression. TOP2A ablation by siRNA corroborates its contribution to apoptosis induced by bDMC. Short-term exposure to bDMC induces retention of TOP2A-DNA intermediates, while longer exposure inhibits TOP2A transcription by affecting expression and sub-cellular localization of NF-Y subunits. ChIP analysis highlighted reduced recruitment of NF-Y to TOP2A regulatory regions, concomitantly to histone deacetylation and decreased gene transcription. Our findings suggest that the dual activity of bDMC on TOP2A represents a novel therapeutic strategy to induce persistent apoptosis in cancer cells and identify NF-Y regulation as a promising approach in anti-cancer therapy.

Topics: Antigens, Neoplasm; Apoptosis; CCAAT-Binding Factor; Cell Proliferation; Colorectal Neoplasms; Curcumin; Diarylheptanoids; DNA Breaks, Double-Stranded; DNA Topoisomerases, Type II; DNA-Binding Proteins; Gene Expression Regulation, Neoplastic; Gene Silencing; HCT116 Cells; Humans; Poly-ADP-Ribose Binding Proteins; Promoter Regions, Genetic; RNA Interference

Inhibition of PMPMEase, a key enzyme in the polyisoprenylation pathway, induces cancer cell death. In this study, purified PMPMEase was inhibited by the chemopreventive agent, curcumin, with a K(i) of 0.3 μM (IC50 = 12.4 μM). Preincubation of PMPMEase with 1 mM curcumin followed by gel-filtration chromatography resulted in recovery of the enzyme activity, indicative of reversible inhibition. Kinetics analysis with N-para-nitrobenzoyl-S-trans,trans-farnesylcysteine methyl ester substrate yielded K M values of 23.6 ± 2.7 and 85.3 ± 15.3 μM in the absence or presence of 20 μM curcumin, respectively. Treatment of colorectal cancer (Caco2) cells with curcumin resulted in concentration-dependent cell death with an EC50 of 22.0 μg/mL. PMPMEase activity in the curcumin-treated cell lysate followed a similar concentration-dependent profile with IC50 of 22.6 μg/mL. In colorectal cancer tissue microarray studies, PMPMEase immunoreactivity was significantly higher in 88.6% of cases compared to normal colon tissues (P < 0.0001). The mean scores ± SEM were 91.7 ± 11.4 (normal), 75.0 ± 14.4 (normal adjacent), 294.8 ± 7.8 (adenocarcinoma), and 310.0 ± 22.6 (mucinous adenocarcinoma), respectively. PMPMEase overexpression in colorectal cancer and cancer cell death stemming from its inhibition is an indication of its possible role in cancer progression and a target for chemopreventive agents.

Topics: Caco-2 Cells; Carboxylic Ester Hydrolases; Colorectal Neoplasms; Curcumin; Gene Expression Regulation, Neoplastic; Humans; Kinetics; Molecular Targeted Therapy; Protein Prenylation

To discuss the biological function and regulation mechanism of curcumin in promoting human colorectal carcinoma (LoVo) cells apoptosis.. Conventional in vitro culture in human colorectal carcinoma cells LoVo, When 80%-90% confluence was reached, cells were treated with curcumin at different concentrations (0-20 mg x L(-1)). Curcumin's effect on cell proliferation level was examined by MTT colorimetry. The ultrastructure of curcumin-treated LoVo cells were observed with transmission electron microscope (TEM). The amount of PI-positive LoVo cells after the curcumin treatment were determined by flow cytometry. The cell apoptosis rate was detected by Annexin V-FITC/PI double staining. The mRNA level of Bax, Bcl-2, Caspase-3 and Bcl-xL were tested by means of RT-PCR.. MTT test indicates curcumin could inhibite the growth and proliferation of LoVo cells in a time- and concentration-dependent manner. TEM examination showed that curcumin can make LoVo cell morphological changes, showing the typical characteristics of apoptotic cells. Flow cytometry instrument analysis showed that curcumin can arrest cell cycle at S phase, and induce apoptosis of LoVo cells. RT-PCR test showed that curcumin can activate the expression of Bax and Caspase-3, inhibit the expression of Bcl-2 and Bcl-xL at the mRNA level.. Curcumin can significantly inhibit the proliferation and induce the apoptosis of human colorectal carcinoma cells LoVo. Such biological effect may be associated with activating Caspase-3 signal channel by activating Bax expression and inhibiting Bcl-2 and Bcl-xL expression. This study lays an important foundation for further discussing the mechanism of curcumin in inducing human colorectal carcinoma LoVo apoptosis.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Curcumin; Dose-Response Relationship, Drug; Humans

Treatment of late stage cancers has proven to be a very difficult task. Targeted therapy and combinatory drug administration may be the solution.. The study was performed to evaluate the therapeutic efficacy of PEG-PE micelles, co-loaded with curcumin (CUR) and doxorubicin (DOX), and targeted with anti-GLUT1 antibody (GLUT1) against HCT-116 human colorectal adenocarcinoma cells both in vitro and in vivo.. HCT-116 cells were treated with non-targeted and GLUT1-targeted CUR and DOX micelles as a single agent or in combination. Cells were inoculated in female nude mice. Established tumors were treated with the micellar formulations at a dose of 4 mg/kg CUR and 0.4 mg/kg DOX every 2 d for a total of 7 injections.. CUR + DOX-loaded micelles decorated with GLUT1 had a robust killing effect even at low doses of DOX in vitro. At the doses chosen, non-targeted CUR and CUR + DOX micelles did not exhibit any significant tumor inhibition versus control. However, GLUT1-CUR and GLUT1-CUR + DOX micelles showed a significant tumor inhibition effect with an improvement in survival.. We showed a dramatic improvement in efficacy between the non-targeted and GLUT1-targeted formulations both in vitro and in vivo. Hence, we confirmed that GLUT1-CUR + DOX micelles are effective and deserve further investigation.

Topics: Adenocarcinoma; Animals; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Curcumin; Doxorubicin; Drug Carriers; Drug Delivery Systems; Female; Glucose Transporter Type 1; HCT116 Cells; Humans; Mice; Mice, Nude; Micelles; Phosphatidylethanolamines; Polyethylene Glycols; Survival Rate; Xenograft Model Antitumor Assays

To investigate the effects of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) deficiency on the cytotoxicity of chemotherapeutic agents toward colorectal cancer cells.. PTEN-deficient colorectal cancer (CRC) cells were generated by human somatic cell gene targeting using the adeno-associated virus system. The cytotoxic effects of compounds including curcumin, 5-fluorouracil (5-FU), dihydroartemisinin (DHA), irinotecan (CPT-11) and oxaliplatin (OXA) on cancer cells were determined using the MTT assay. Enhanced cytotoxicity of curcumin in PTEN-deficient CRC cells was observed, and this was confirmed using clonogenic assays. Apoptosis and cell cycle progression were analyzed by flow cytometry. Levels of apoptosis and cell cycle-related proteins were examined by Western blotting.. We developed an isogenic set of CRC cell lines that differed only in their PTEN status. Using this set of cell lines, we found that disruption of the PTEN gene had no effect on the sensitivity of CRC cells to 5-FU, CPT-11, DHA, or OXA, whereas PTEN disruption increased the sensitivity of CRC cells to curcumin. Loss of PTEN did not alter the curcumin-induced apoptosis in CRC cells. However, PTEN deficiency led to an altered pattern of curcumin-mediated cell cycle arrest. In HCT116 PTEN (+/+) cells, curcumin caused a G2/M phase arrest, whereas it caused a G0/G1 phase arrest in HCT116 PTEN (-/-) cells. Levels of cell cycle-related proteins were consistent with these respective patterns of cell cycle arrest.. Curcumin shows enhanced cytotoxicity toward PTEN-deficient cancer cells, suggesting that it might be a potential chemotherapeutic agent for cancers harboring PTEN mutations.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Cell Cycle Checkpoints; Cell Survival; Colorectal Neoplasms; Curcumin; Dose-Response Relationship, Drug; Down-Regulation; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Gene Knockout Techniques; HCT116 Cells; Humans; PTEN Phosphohydrolase; Time Factors

Clinical application of curcumin has been limited due to poor aqueous solubility and consequently minimal systemic bioavailability. We investigated the preparation of curcumin-loaded micelles based on amphiphilic Pluronic/Polycaprolactone (Pluronic/PCL) block copolymer, which proved to be efficient in enhancing curcumin's aqueous solubility. Curcumin-loaded micelles of size below 200 nm was characterized by dynamic light scattering and transmission electron microscopy. The critical micelle concentration (CMC) of the amphiphilic polymer was determined using pyrene as a fluorescent probe. Hemolysis and aggregation studies were investigated to evaluate the blood compatibility of the micelles. Sodium dodecyl sulphate polyacrylamide gel electrophoresis was performed to study the stability of the micelles toward plasma proteins. In vitro cytotoxicity and cellular uptake of the curcumin-loaded micelles were demonstrated in colorectal adenocarcinoma (Caco2) cells. The results indicated that Pluronic/PCL micelles could be a promising candidate for curcumin delivery to cancer cells.

Topics: Adenocarcinoma; Antineoplastic Agents; Blood Platelets; Caco-2 Cells; Colorectal Neoplasms; Curcumin; Drug Carriers; Erythrocytes; Hemolysis; Humans; Micelles; Particle Size; Poloxamer

The chemopreventive agent curcumin has anti-proliferative effects in many tumour types, but characterization of cell cycle arrest, particularly with physiologically relevant concentrations, is still incomplete. Following oral ingestion, the highest concentrations of curcumin are achievable in the gut. Although it has been established that curcumin induces arrest at the G(2)/M stage of the cell cycle in colorectal cancer lines, it is not clear whether arrest occurs at the G(2)/M transition or in mitosis. To elucidate the precise stage of arrest, we performed a direct comparison of the levels of curcumin-induced G(2)/M boundary and mitotic arrest in eight colorectal cancer lines (Caco-2, DLD-1, HCA-7, HCT116p53+/+, HCT116p53(-)/(-), HCT116p21(-)/(-), HT-29 and SW480). Flow cytometry confirmed that these lines underwent G(2)/M arrest following treatment for 12h with clinically relevant concentrations of curcumin (5-10 μM). In all eight lines, the majority of this arrest occurred at the G(2)/M transition, with a proportion of cells arresting in mitosis. Examination of the mitotic index using fluorescence microscopy showed that the HCT116 and Caco-2 lines exhibited the highest levels of curcumin-induced mitotic arrest. Image analysis revealed impaired mitotic progression in all lines, exemplified by mitotic spindle abnormalities and defects in chromosomal congression. Pre-treatment with inhibitors of the DNA damage signalling pathway abrogated curcumin-induced mitotic arrest, but had little effect at the G(2)/M boundary. Moreover, pH2A.X staining seen in mitotic, but not interphase, cells suggests that this aberrant mitosis results in DNA damage.

Topics: Antineoplastic Agents; Apoptosis; Aurora Kinases; Blotting, Western; Cell Cycle; Cell Proliferation; Chromosome Segregation; Colorectal Neoplasms; Curcumin; DNA Damage; Flow Cytometry; Humans; Immunoenzyme Techniques; Mitosis; Protein Serine-Threonine Kinases; Signal Transduction; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Spindle Apparatus; Tumor Cells, Cultured

Colorectal cancer (CRC) is the third leading cause of cancer death in Taiwan; it ranks top three in the cancer mortality rate. Curcuminoids are derived from the rhizome of Curcuma longa. It has shown anti-cancer activity and apoptosis induction in a variety of cancer cell lines. This aims to study the potential of Poloxamer 407 as the thermogelling and mucoadhesive polymer for development of a site-targeting delivery system to enhance the localized delivery of curcuminoids to the colorectal cells for CRC chemotherapy.. The mucoadhesive strength and rheological properties were measured as a function of poloxamer loaded with curcuminoids.. The gelation temperature of Poloxamer 407 was found to vary with its concentration and start gelling at 37°C at the concentration of 15.5% (w/v). To ensure gelation at physiological temperature after intra-rectal application, gelation temperature was determined by rheological measurement as well as by its physical appearance. The results indicated that its mucoadhesive strength also shows a dependency on temperature, which appears to be related to the increment in the maximum strength and average strength of the polymer.. The results have suggested that Poloxamer 407 could be a potential thermogelling and mucoadhesive polymer for the development of a site-targeting colorectal drug delivery system for curcuminoids in colorectal cancer therapy.

Topics: Adhesives; Aged; Aged, 80 and over; Biocompatible Materials; Cell Death; Cell Survival; Chemoprevention; Colorectal Neoplasms; Curcumin; Drug Delivery Systems; Female; Gels; Humans; Intestinal Mucosa; Male; Materials Testing; Middle Aged; Poloxamer; Suppositories; Temperature

Our study shows that coadministration of curcumin and an orally bioactive alkylphospholipid perifosine results in a significant increase in colorectal cancer cell apoptosis and a marked inhibition of cell growth both in vitro and in vivo. This novel combinatorial regimen leads to changes of multiple cell signaling pathways including inactivation of Akt and nuclear factor-κB as well as activation of c-Jun N-terminal kinases and endoplasmic reticulum stress. Further, perifosine and curcumin synergistically increase intracellular level of reactive oxygen species and ceramide, and downregulate the expression of cyclin D1 and Bcl-2 in colorectal cancer cells. These changes at molecular level together account for the cancer cell apoptosis and growth inhibition. We conclude that perifosine sensitizes colorectal cancer cells to curcumin by modulating multiple signaling pathways. Adding perifosine with curcumin may represent an effective therapy regimen against colorectal cancers, and possible other aggressive tumors.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Caco-2 Cells; Cell Death; Cell Line, Tumor; Cell Proliferation; Ceramides; Colorectal Neoplasms; Curcumin; Cyclin D1; Down-Regulation; Drug Synergism; Endoplasmic Reticulum; Female; HCT116 Cells; HT29 Cells; Humans; I-kappa B Proteins; JNK Mitogen-Activated Protein Kinases; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, SCID; Multiprotein Complexes; NF-kappa B; NF-KappaB Inhibitor alpha; Phosphorylation; Phosphorylcholine; Proteins; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species; Signal Transduction; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays

Curcumin, a natural polyphenol derived from the rhizome of Curcuma longa, is a potent anticancer agent, which restricts tumor cell growth both in vitro and in vivo. Thus far curcumin was shown to induce death of cancer cells. This study reports the induction of cellular senescence of human colon cancer cells HCT116 upon curcumin treatment. The SA-β-galactosidase activation was observed both in p53+/+ and p53-/- cells, however the latter ones were less sensitive to the prosenescent activity of curcumin. Upregulation of p53 and p21 proteins was observed in p53+/+ HCT116, while p53-independent induction of p21 was noticed in p53-/- HCT116. Moreover, the senescence of HCT116 cells was accompanied by autophagy, that was confirmed by electron microscopy observations of autophagosomes in the curcumin-treated cells as well as LC3-II expression, punctue staining of LC3 and increased content of acidic vacuoles. Inhibition of autophagy, due to the diminished expression of ATG5 by RNAi decreased the number of senescent cells induced by curcumin, but did not lead to increased cell death. Altogether, we demonstrated a new antitumor activity of curcumin leading to cancer cell senescence and revealed the presence of a functional link between senescence and autophagy in curcumin-treated cells.

Topics: Antineoplastic Agents; Autophagy; Autophagy-Related Protein 5; beta-Galactosidase; Cell Proliferation; Cellular Senescence; Colorectal Neoplasms; Curcumin; Gene Silencing; HCT116 Cells; Humans; Microtubule-Associated Proteins; Tumor Suppressor Protein p53; Vacuoles

Curcumin has extraordinary anticancer properties but has limited use due to its insolubility in water and instability, which leads to low systemic bioavailability. We have developed a novel nanoparticulate formulation of curcumin encapsulated in stearic acid-g-chitosan oligosaccharide (CSO-SA) polymeric micelles to overcome these hurdles.. The synthesized CSO-SA copolymer was able to self-assemble to form nanoscale micelles in aqueous medium. The mean diameter of the curcumin-loaded CSO-SA micelles was 114.7 nm and their mean surface potential was 18.5 mV. Curcumin-loaded CSO-SA micelles showed excellent internalization ability that increased curcumin accumulation in cancer cells. Curcumin-loaded CSO-SA micelles also had potent antiproliferative effects on primary colorectal cancer cells in vitro, resulting in about 6-fold greater inhibition compared with cells treated with a solution containing an equivalent concentration of free curcumin. Intravenous administration of curcumin-loaded CSO-SA micelles marginally suppressed tumor growth but did not increase cytotoxicity to mice, as confirmed by no change in body weight. Most importantly, curcumin-loaded CSO-SA micelles were effective for inhibiting subpopulations of CD44(+)/CD24(+) cells (putative colorectal cancer stem cell markers) both in vitro and in vivo.. The present study identifies an effective and safe means of using curcumin-loaded CSO-SA micelles for cancer therapy.

Topics: Animals; Antineoplastic Agents; Body Weight; CD24 Antigen; Cell Survival; Chitosan; Colorectal Neoplasms; Curcumin; Drug Carriers; Drug Stability; Flow Cytometry; Humans; Hyaluronan Receptors; Mice; Micelles; Nanoparticles; Neoplastic Stem Cells; Particle Size; Random Allocation; Solubility; Tumor Burden; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Curcumin has promising potential in cancer prevention and therapy by interacting with proteins and modifying their expression and activity, which includes transcription factors, inflammatory cytokines and factors of cell survival, proliferation and angiogenesis. miR-21 is overexpressed in many tumours, promoting progression and metastasis. In the present study, we examined the potential of curcumin to regulate miR-21, tumour growth, invasion and in vivo metastasis in colorectal cancer. In Rko and HCT116 cells, we identified two new transcriptional start sites of the miR-21 gene and delineated its promoter region. PMA stimulation induced miR-21 expression via motifs bound with AP-1 (activator protein 1) transcription factors. Curcumin treatment reduced miR-21 promoter activity and expression in a dose-dependent manner by inhibiting AP-1 binding to the promoter, and induced the expression of the tumour suppressor Pdcd4 (programmed cell death protein 4), which is a target of miR-21. Curcumin-treated Rko and HCT116 cells were arrested in the G2/M phase with increasing concentrations. Furthermore, curcumin inhibited tumour growth, invasion and in vivo metastasis in the chicken-embryo-metastasis assay [CAM (chorionallantoic membrane) assay]. Additionally, curcumin significantly inhibited miR-21 expression in primary tumours generated in vivo in the CAM assay by Rko and HCT116 cells (P<0.00006 and P<0.035 respectively). Taken together, this is the first paper to show that curcumin inhibits the transcriptional regulation of miR-21 via AP-1, suppresses cell proliferation, tumour growth, invasion and in vivo metastasis, and stabilizes the expression of the tumour suppressor Pdcd4 in colorectal cancer.

Topics: Animals; Antineoplastic Agents; Apoptosis Regulatory Proteins; Cell Cycle; Chick Embryo; Colorectal Neoplasms; Curcumin; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humans; MicroRNAs; Neoplasm Invasiveness; Neoplasm Metastasis; RNA-Binding Proteins; Transcriptional Activation

The aims of this study were to determine potency of oxaliplatin in combination with curcumin in oxaliplatin-resistant cell lines in vitro and to evaluate the efficacy of a novel curcumin formulation (Meriva®) alone and in combination with oxaliplatin in colorectal tumor-bearing mice, exploring relevant pharmacodynamic markers in vivo. Oxaliplatin-resistant HCT116 p53wt and p53(-/-) cell lines were generated, and the effects of oxaliplatin in combination with curcumin on resistance- and proliferation-associated proteins investigated. Eighty nude mice were implanted with HCT116 p53wt colorectal cancer cells before randomization into the following treatment groups: control; Meriva only; oxaliplatin only; Meriva + oxaliplatin. Tumor volume was assessed, as was the expression of Ki-67, cleaved caspase-3 and Notch-1. Curcumin in combination with oxaliplatin was able to decrease proliferative capacity of oxaliplatin-resistant p53 wildtype and p53(-/-) cell lines more effectively than oxaliplatin alone. It also decreased markers associated with proliferation. After 21 days of treatment in the xenograft model, the order of efficacy was combination > Meriva > oxaliplatin > control. The decrease in tumor volume when compared to vehicle-treated animals was 53, 35 and 16%, respectively. Ki-67 and Notch-1 immunoreactivity was decreased by the combination when compared to vehicle-treated animals, with cleaved caspase-3 rising by 4.4-fold. Meriva did not adversely affect the DNA-platinating ability of oxaliplatin. Curcumin enhanced the cytotoxicity of oxaliplatin in models of oxaliplatin resistance in vitro. In vivo, Meriva greatly enhanced oxaliplatin efficacy, without affecting the mode of action of oxaliplatin. Addition of formulated curcumin to oxaliplatin-based chemotherapy regimens has the potential for clinical benefit.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Curcumin; Drug Resistance, Neoplasm; Drug Synergism; Female; HCT116 Cells; Humans; Mice; Mice, Nude; Organoplatinum Compounds; Oxaliplatin; Random Allocation; Xenograft Model Antitumor Assays

Curcumin is a polyphenol with a variety of pharmacologic effects. We evaluate the effect of dietary curcumin on the severity of repeated colitis-associated colorectal cancer.. Six-week-old C57BL/6 mice were randomized into two dietary groups: standard diet and curcumin at 0.6% diet. The mice were exposed to 15 cycles of 0.7% dextran sodium sulphate for 1 week followed by distilled water for 10 days. After curcumin diet, the disease activity index presented a statistical reduction in the last cycles, macroscopic tumors were not seen and the microscopic study showed minor neoplasic lesions with respect to standard diet-group. β-Catenin translocation to the cytoplasm and/or nucleus was observed in the tumor tissue, but this translocation and its intensity were significantly minor in the curcumin diet-DSS animals. Cytokines as tumor necrosis factor-α and IFN-γ were significantly diminished in DSS-animals fed with curcumin. Conversely, non-modification of p53 expression was observed and cyclo-oxygenase-2 and inducible nitric oxide synthase were significantly reduced in the curcumin diet-DSS group.. We demonstrate the protective/preventive effect of curcumin in the progression of colorectal cancer associated to colitis, which was correlated with a lowered immunoreactivity of ß-catenin, a non-modification of p53 expression, a reduction of proinflammatory cytokine levels and a decrease of inflammatory protein overexpression.

Topics: Animals; beta Catenin; Cell Nucleus; Colitis; Colon; Colorectal Neoplasms; Curcumin; Cyclooxygenase 2; Cytokines; Cytoplasm; Diet; Female; Mice; Mice, Inbred C57BL; Nitric Oxide Synthase Type II; Precancerous Conditions; Protein Transport; Random Allocation; Severity of Illness Index; Tumor Suppressor Protein p53

Curcumin has been associated with the treatment of various diseases in traditional medicine, among them cancer. The major problems that prevent its approval as therapeutic agent are its low water solubility and its relatively low in vivo bioavailability. Liposomes are considered as effective drug carriers because of their ability to solubilize hydrophobic compounds and to alter their pharmacokinetic properties. The purpose of this study was the development of lyophilised liposomal curcumin fully characterized in terms of its physical properties [(zeta-potential, size, size distribution and Polydispercity index (PI)], and to evaluate its in vitro cytotoxic against colorectal cancer cell lines in a short-term and in a long-term (clonogenic) assay. Curcumin was incorporated in egg-phosphatidylcholine (EPC) liposomes at a drug to lipid molar ratio 1:14 achieving high incorporation efficiency close to 85%. The liposomal curcumin was lyophilized preserving thus its stability. The reconstitution of the formulation resulted in the original liposomal suspension. The release in FBS showed a plateau near 14% at 96 hours of incubation. The in vitro studies against colorectal cancer cell lines have shown that liposomes improve the activity of curcumin especially in the long-term assay and the liposomal formulation found to be more potent against HCT116 and HCT15, cell lines which express the MDR phenotype. EPC liposomal curcumin in a molar ratio of curcumin/EPC 1:14 has shown improved cytotoxic activity versus free curcumin against colorectal cancer cell lines. In vivo studies based on the recent findings are in progress in our laboratory.

Topics: Antineoplastic Agents; Cell Line, Tumor; Colorectal Neoplasms; Curcumin; Drug Delivery Systems; Freeze Drying; Humans; In Vitro Techniques; Lecithins; Liposomes; Nanotechnology; Tumor Stem Cell Assay

The only FDA approved medication for colorectal cancer (CRC) prevention is celecoxib. Its adverse effects underline the need for safer drugs. Polyphenols like resveratrol are in clinical trials for this purpose. This study aimed at examining effects of resveratrol alone and in combination with curcumin or chrysin on UGT induction in Caco-2 cells. Phytochemical combinations were selected using drug combination analyses of various anti-proliferation ratios of resveratrol+curcumin and resveratrol+chrysin.. Cell proliferation and UGT1A1 induction assays were carried out with individual polyphenols and combinations. Cell viability was determined with AlamarBlue assays. UGT1A1 mRNA was quantified via real time RT-PCR. UGT activity was determined with 4-methylumbelliferone (4MU) glucuronidation.. Cell proliferation IC(50) estimates (± SE) for resveratrol, curcumin and chrysin were 20.8 ± 1.2, 20.1 ± 1.1 and 16.3 ± 1.3μM respectively. Combination of anti-proliferative effects showed additivity for resveratrol+chrysin and resveratrol+curcumin. Resveratrol at its IC(50) mediated a four-fold induction of UGT1A1 mRNA in a concentration independent manner. Chrysin at its IC(50) induced UGT1A1 expression seven-fold while Curcumin at its IC(90) mediated a two-fold induction. The 20 μM:40μ M resveratrol+curcumin and 20 μM :32 μM resveratrol+chrysin combinations mediated the greatest increases in mRNA expression (12 and 22 folds respectively). Significant increase in 4-MU glucuronidation was observed with combinations exhibiting maximal mRNA induction.. Phytochemical combinations can offer greater chemoprevention than single agents. These chemicals might offer safer options than present synthetic therapeutics for CRC prevention.

Topics: Anticarcinogenic Agents; Caco-2 Cells; Cell Proliferation; Cell Survival; Colorectal Neoplasms; Curcumin; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Enzyme Induction; Flavonoids; Glucuronides; Glucuronosyltransferase; Humans; Inhibitory Concentration 50; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stilbenes

Curcumin (CUR), a polyphenol derived from the plant Curcuma longa, displays potential anti-cancer activity. One of the mechanisms stems from its ability to elicit cell cycle arrest followed by suppression of cell proliferation. Herein, we reported that CUR significantly induced DNA damage and mediated S and G2/M phase arrest in colorectal carcinoma HCT116 cells. Unlike etoposide, a classical topoisomerase II inhibitor, CUR-triggered G2/M phase arrest was hardly reversed by caffeine (CAFF) which is an inhibitor of activated ataxia-telangiectasia-mutated (ATM)/ATM- and Rad3-related (ATR), indicating that ATM and ATR signaling pathways may be not involved in CUR-mediated S and G2/M phase arrest in HCT116 cells. Furthermore, we demonstrated that CUR caused mitosis arrest in HCT116 cells by using mitotic protein monoclonal antibody-2 as a mitosis marker and the surface plasmon resonance assay. The findings provide new mechanisms of cell proliferation inhibition triggered by CUR in HCT116 cells.

Topics: Antineoplastic Agents; Caffeine; Colorectal Neoplasms; Curcumin; DNA Damage; G2 Phase; HCT116 Cells; Humans; Mitosis; Phosphodiesterase Inhibitors; S Phase; Tubulin

The use of sulindac sulfone (SFN) for colorectal cancer (CRC) therapy is limited due to its toxicity. The present study was carried out to examine whether curcumin, a novel chemopreventive agent, can potentiate the effects of low dosages of SFN in CRC treatment.. HT-29 CRC cells were exposed to SFN (200 - 400 microM), curcumin (5 - 10 microM) or their combination. The cytotoxic effects of the drugs were evaluated using growth inhibition assays. Annexin V/PI and cell cycle analysis were employed to study the mechanism of action of the drugs. The therapeutic efficacy of the drugs in vivo was examined using the aberrant crypt foci (ACF) model. The treatment groups included eight rats/group.. Treatment of cells with curcumin and SFN resulted in a synergistic inhibitory effect of 50 - 90% (p < 0.005) on cell growth. Growth inhibition was associated with inhibition of proliferation, G2/M arrest and induction of apoptosis. Administration of curcumin (0.6%) and SFN (0.06%) to 1, 2-dimethylhydrazine treated rats significantly reduced (by 75%, p < 0.01) the number of ACF.. Curcumin augments the therapeutic effects of SFN. This may be clinically important since the addition of curcumin to low dosages of SFN may encourage a safer and potent combinatorial treatment regimen for CRC.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Cycle; Cell Proliferation; Colorectal Neoplasms; Curcumin; Dose-Response Relationship, Drug; Drug Synergism; HT29 Cells; Humans; Male; Precancerous Conditions; Rats; Rats, Wistar; Sulindac

Colorectal carcinoma is one of the major causes of morbidity and mortality in the Western World. Novel therapeutic approaches are needed for colorectal carcinoma. Curcumin, the active component and yellow pigment of turmeric, has been reported to have several anti-cancer activities including anti-proliferation, anti-invasion, and anti-angiogenesis. Clinical trials have suggested that curcumin may serve as a potential preventive or therapeutic agent for colorectal cancer.. We compared the inhibitory effects of curcumin and novel structural analogues, GO-Y030, FLLL-11, and FLLL-12, in three independent human colorectal cancer cell lines, SW480, HT-29, and HCT116. MTT cell viability assay was used to examine the cell viability/proliferation and western blots were used to determine the level of PARP cleavages. Half-Maximal inhibitory concentrations (IC50) were calculated using Sigma Plot 9.0 software.. Curcumin inhibited cell viability in all three of the human colorectal cancer cell lines studied with IC50 values ranging between 10.26 microM and 13.31 microM. GO-Y030, FLLL-11, and FLLL-12 were more potent than curcumin in the inhibition of cell viability in these three human colorectal cancer cell lines with IC50 values ranging between 0.51 microM and 4.48 microM. In addition, FLLL-11 and FLLL-12 exhibit low toxicity to WI-38 normal human lung fibroblasts with an IC-50 value greater than 1,000 microM. GO-Y030, FLLL-11, and FLLL-12 are also more potent than curcumin in the induction of apoptosis, as evidenced by cleaved PARP and cleaved caspase-3 in all three human colorectal cancer cell lines studied.. The results indicate that the three curcumin analogues studied exhibit more potent inhibitory activity than curcumin in human colorectal cancer cells. Thus, they may have translational potential as chemopreventive or therapeutic agents for colorectal carcinoma.

Topics: Antineoplastic Agents; Blotting, Western; Caspase 3; Cell Line; Cell Line, Tumor; Cell Survival; Colorectal Neoplasms; Curcumin; Growth Inhibitors; HCT116 Cells; HT29 Cells; Humans; Inhibitory Concentration 50; Molecular Structure; Poly(ADP-ribose) Polymerases

Curcumin (diferuloylmethane) has chemopreventive and chemotherapeutic potentials against various types of cancers. We have developed a series of curcumin analogs to improve its low bioavailability by enhancing its potentials. The newly synthesized analog GO-Y030 [(1E, 4E)-1,5-bis-(3,5(-bismethoxymethoxyphenyl) penta-1,4-dien-3-one] showed a 30-fold greater growth suppression in vitro via similar molecular mechanisms to curcumin. The availability of this analog was examined by using a mouse model harboring the germ-line mutation of Apc, Apc(580D/+), in vivo. Apc(580D/+) mice had a very limited survival time with an intestinal obstruction due to polyposis. The average tumor number in mice fed GO-Y030 was reduced to 61.2% of those that were fed the basal diet (P < 0.05). Compared with Apc(580D/+) mice fed the basal diet (median survival time = 166.5 days), a significantly prolonged lifespan (213 days) was observed in Apc(580D/+) mice fed GO-Y030. The chemopreventive effect with GO-Y030 was improved, compared with curcumin (191 days). The survival benefit corresponded to the diminished intestinal tumor incidence in Apc(580D/+) mice fed GO-Y030. No adverse reactions were observed, judging from body weight or biochemical data concerning liver and renal damage. Degradation of accumulated beta-catenin with curcumin is one of the major mechanisms of chemoprevention in colorectal carcinogenesis. It was demonstrated that the number of beta-catenin-positive adenoma cells in Apc(580D/+) mice fed GO-Y030 was reduced.

Topics: Adenoma; Animals; Benzene Derivatives; beta Catenin; Cell Transformation, Neoplastic; Colorectal Neoplasms; Curcumin; Disease Models, Animal; Genetic Predisposition to Disease; Ketones; Mice; Molecular Structure; Survival Rate

Because of the poor prognosis and the development of resistance against chemotherapeutic drugs, the current treatment for advanced metastatic colorectal cancer (CRC) is ineffective. Whether curcumin (a component of turmeric) can potentiate the effect of capecitabine against growth and metastasis of CRC was investigated. The effect of curcumin on proliferation of CRC cell lines was examined by mitochondrial dye-uptake assay, apoptosis by esterase staining, nuclear factor-kappaB (NF-kappaB) by electrophoretic mobility shift assay and gene expression by Western blot analysis. The effect of curcumin on the growth and metastasis of CRC was also examined in orthotopically implanted tumors in nude mice. In vitro, curcumin inhibited the proliferation of human CRC cell lines, potentiated capecitabine-induced apoptosis, inhibited NF-kappaB activation and suppressed NF-kappaB-regulated gene products. In nude mice, the combination of curcumin and capecitabine was found to be more effective than either agent alone in reducing tumor volume (p = 0.001 vs. control; p = 0.031 vs. capecitabine alone), Ki-67 proliferation index (p = 0.001 vs. control) and microvessel density marker CD31. The combination treatment was also highly effective in suppressing ascites and distant metastasis to the liver, intestines, lungs, rectum and spleen. This effect was accompanied by suppressed expression of activated NF-kappaB and NF-kappaB-regulated gene products (cyclin D1,c-myc, bcl-2, bcl-xL, cIAP-1, COX-2, ICAM-1, MMP-9, CXCR4 and VEGF). Overall, our results suggest that curcumin sensitizes CRC to the antitumor and antimetastatic effects of capecitabine by suppressing NF-kappaB cell signaling pathway.

Topics: Animals; Antineoplastic Agents; Apoptosis; Capecitabine; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Curcumin; Cyclin D1; Cyclooxygenase 2; Deoxycytidine; Drug Synergism; Fluorouracil; Gene Expression Regulation, Neoplastic; Humans; Male; Matrix Metalloproteinase 9; Mice; Neoplasm Metastasis; NF-kappa B; Receptors, CXCR4; Vascular Endothelial Growth Factor A

Curcumin, a natural polyphenol product of the plant Curcuma longa, has been shown to inhibit the growth and progression of colorectal cancer; however, the anticancer mechanism of curcumin remains to be elucidated.. Colorectal cancer cells were treated with curcumin and changes in proliferation, protein and mRNA levels were analyzed.. Curcumin inhibited proliferation of colorectal cancer cells. This effect was mediated by inhibition of mammalian target of rapamycin (mTOR) signaling as evidenced by decreased phosphorylation of downstream effectors of mTOR complex 1 (mTORC1), p70S6K and 4E-BP1. Curcumin decreased total expression of mTOR, Raptor and Rictor protein and mRNA levels. Surprisingly, curcumin induced phosphorylation of Akt(Ser 473); this effect may be attributed to a decrease in levels of the PHLPP1 phosphatase, an inhibitor of Akt.. Our data suggest that curcumin, a natural compound, may exert its antiproliferative effects by inhibition of mTOR signaling and thus may represent a novel class of mTOR inhibitor.

Topics: Adaptor Proteins, Signal Transducing; Antineoplastic Agents; Blotting, Western; Cell Cycle Proteins; Cell Proliferation; Colorectal Neoplasms; Curcumin; Humans; Mechanistic Target of Rapamycin Complex 1; Multiprotein Complexes; Phosphoproteins; Phosphorylation; Proteins; Proto-Oncogene Proteins c-akt; Reverse Transcriptase Polymerase Chain Reaction; Ribosomal Protein S6 Kinases, 70-kDa; RNA, Messenger; TOR Serine-Threonine Kinases; Transcription Factors; Tumor Cells, Cultured

Radiation therapy is an integral part of the preoperative treatment of rectal cancers. However, only a minority of patients achieve a complete pathologic response to therapy because of resistance of these tumors to radiation therapy. This resistance may be mediated by constitutively active pro-survival signaling pathways or by inducible/acquired mechanisms in response to radiation therapy. Simultaneous inhibition of these pathways can sensitize these tumors to radiation therapy.. Human colorectal cancer cells were exposed to clinically relevant doses of gamma rays, and the mechanism of their radioresistance was investigated. We characterized the transcription factor nuclear factor-kappaB (NF-kappaB) activation as a mechanism of inducible radioresistance in colorectal cancer and used curcumin, the active ingredient in the yellow spice turmeric, to overcome this resistance.. Curcumin inhibited the proliferation and the post-irradiation clonogenic survival of multiple colorectal cancer cell lines. Radiation stimulated NF-kappaB activity in a dose- and time-dependent manner, whereas curcumin suppressed this radiation-induced NF-kappaB activation via inhibition of radiation-induced phosphorylation and degradation of inhibitor of kappaB alpha, inhibition of inhibitor of kappaB kinase activity, and inhibition of Akt phosphorylation. Curcumin also suppressed NF-kappaB-regulated gene products (Bcl-2, Bcl-x(L), inhibitor of apoptosis protein-2, cyclooxygenase-2, and cyclin D1).. Our results suggest that transient inducible NF-kappaB activation provides a prosurvival response to radiation that may account for development of radioresistance. Curcumin blocks this signaling pathway and potentiates the antitumor effects of radiation therapy.

Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Colorectal Neoplasms; Curcumin; Dose-Response Relationship, Drug; Enzyme Inhibitors; Gene Expression Regulation; HT29 Cells; Humans; Neoplasm Proteins; NF-kappa B; Phosphorylation; Proto-Oncogene Proteins c-akt; Radiation Tolerance; Radiation-Sensitizing Agents; Rectal Neoplasms

The chemical compound delta-elemene, isolated from the Chinese herbal medicine plant Curcuma Wenyujin, has been known to exert antitumor activity. In this study we demonstrated that apoptotic cell death induced by delta-elemene in DLD-1 cells was concentration-and time-dependent, and had little inhibition of the normal human liver cell line WRL-68. Apoptosis was further confirmed and quantified by DNA fragmentation ELISA, Annexin V (AnV) binding of externalized phosphatidylserine and the mitochondrial probe JC-1 using flow cytometry. The rapid increase in intracellular reactive oxygen species (ROS) levels was involved in the mechanism of cell death. Western blot analysis demonstrated that delta-elemene activated the caspase-signaling pathway, leading to the proteolysis conversion of pro-caspase-3 to activate caspase-3, and the subsequent cleavage of the caspase substrate PARP. In the process of the induction of apoptotic cell death, Bax translocated into mitochondria, a reduction in Deltapsim was observed and a release of cytochrome c and apoptosis inducing factor (AIF) from mitochondria into the cytosol occurred, indicating that cell death induced by delta-elemene was through a mitochondrial-mediated pathway.

Topics: Adenocarcinoma; Antineoplastic Agents, Phytogenic; Apoptosis; Caspase 3; Cell Line, Tumor; Colorectal Neoplasms; Curcuma; Dose-Response Relationship, Drug; Humans; Mitochondria; Poly(ADP-ribose) Polymerases; Reactive Oxygen Species; Sesquiterpenes; Time Factors

Familial Adenomatous Polyposis (FAP) is a model for the adenoma-carcinoma sequence in several respects. One important area in which FAP serves as a model is chemoprevention. Early prevention trials mainly utilized micronutrients and were largely unsuccessful in preventing or causing regression of adenomas. A new era was ushered in by the recognition that antiarthritic doses of a nonsteroidal anti-inflammatory agent (NSAID), sulindac, could actually induce regression of colorectal adenomas in patients with FAP. Follow-up studies showed positive but variable long-term efficacy for colorectal adenomas, but sulindac appears to lack significant benefit in regressing duodenal adenomas or preventing initial occurrence of adenomas in APC mutation carriers. Due to the well-known side effects of traditional NSAIDs, selective COX-2 inhibitors have been studied rather extensively. Celecoxib has shown benefit in regressing colorectal adenomas and appears to have some duodenal activity as well. Rofecoxib, in smaller trials, showed efficacy as well. However, the entire field of NSAID research in chemoprevention is undergoing reexamination in light of recent demonstration of cardiovascular toxicity in nonfamilial or sporadic adenoma prevention trials. Whether NSAIDs will have a significant future in FAP chemoprevention will depend on a sober assessment of risks and benefits. These same issues will likely foster a more intensive search for new agents. FAP will undoubtedly continue to have a lead role in the testing of new agents, both in the interest of FAP management as such, and in anticipation of trials in nonfamilial adenomas, a problem with even greater societal impact. The historical development of chemoprevention in FAP will be presented, with an emphasis on issues of trial design.

Topics: Adenomatous Polyposis Coli; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Ascorbic Acid; Celecoxib; Chemoprevention; Clinical Trials as Topic; Colorectal Neoplasms; Curcumin; Cyclooxygenase 2 Inhibitors; Drug Therapy, Combination; Eflornithine; Humans; Lactones; Pyrazoles; Sulfonamides; Sulfones; Sulindac; Vitamins

Curcumin (diferuloylmethane), which has been shown to inhibit growth of transformed cells, has no discernible toxicity and achieves high levels in colonic mucosa. 5-fluorouracil (5-FU) or 5-FU plus oxaliplatin (FOLFOX) remains the backbone of colorectal cancer chemotherapeutics, but with limited success. The present investigation was, therefore, undertaken to examine whether curcumin in combination with conventional chemotherapeutic agent(s)/regimen will be a superior therapeutic strategy for colorectal cancer. Indeed, results of our in vitro studies demonstrated that curcumin together with FOLFOX produced a significantly greater inhibition (p < 0.01) of growth and stimulated apoptosis (p < 0.001) of colon cancer HCT-116 and HT-29 cells than that caused by curcumin, 5-FU, curcumin + 5-FU or FOLFOX. These changes were associated with decreased expression and activation (tyrosine phosphorylation) of EGFR, HER-2, HER-3 (72-100%) and IGF-1R (67%) as well as their downstream effectors such as Akt and cycloxygenase-2 (51-97%). Furthermore, while these agents produced a 2-3-fold increase in the expression of IGF-binding protein-3 (IGFBP-3), curcumin together with FOLFOX caused a 5-fold increase in the same, when compared to controls. This in turn led to increased sequestration of IGF by IGFBP-3 rendering IGF-1 unavailable for binding to and activation of IGF-1R. We conclude that the superior effects of the combination therapy of curcumin and FOLFOX are due to attenuation of EGFRs and IGF-1R signaling pathways. We also suggest that inclusion of curcumin to the conventional chemotherapeutic agent(s)/regimen could be an effective therapeutic strategy for colorectal cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Colorectal Neoplasms; Curcumin; Cyclooxygenase 2; Dose-Response Relationship, Drug; Drug Synergism; ErbB Receptors; Fluorouracil; Gene Expression Regulation, Neoplastic; Humans; Insulin-Like Growth Factor Binding Protein 3; Organoplatinum Compounds; Oxaliplatin; Proto-Oncogene Proteins c-akt; Receptor, IGF Type 1

How colorectal cancer develops resistance to gamma-radiation is not fully understood, but the transcription factor nuclear factor-kappaB (NF-kappaB) and NF-kappaB-regulated gene products have been proposed as mediators. Because curcumin, a component of turmeric (Curcuma longa), has been shown to suppress NF-kappaB activation, whether it can sensitize the colorectal cancer to gamma-radiation was investigated in colorectal cancer xenografts in nude mice.. We established HCT 116 xenograft in nude mice, randomized into four groups, and treated with vehicle (corn oil), curcumin, gamma-radiation, and curcumin in combination with gamma-radiation. NF-kappaB modulation was ascertained using electrophoretic mobility shift assay and immunohistochemistry. Markers of proliferation, angiogenesis, and invasion were monitored by immunohistochemistry and Western blot analysis.. Curcumin significantly enhanced the efficacy of fractionated radiation therapy by prolonging the time to tumor regrowth (P=0.02) and by reducing the Ki-67 proliferation index (P<0. 001). Moreover, curcumin suppressed NF-kappaB activity and the expression of NF-kappaB-regulated gene products (cyclin D1, c-myc, Bcl-2, Bcl-xL, cellular inhibitor of apoptosis protein-1, cyclooxygenase-2, matrix metalloproteinase-9, and vascular endothelial growth factor), many of which were induced by radiation therapy and mediate radioresistance. The combination of curcumin and radiation therapy also suppressed angiogenesis, as indicated by a decrease in vascular endothelial growth factor and microvessel density (P=0.002 versus radiation alone).. Collectively, our results suggest that curcumin potentiates the antitumor effects of radiation therapy in colorectal cancer by suppressing NF-kappaB and NF-kappaB-regulated gene products, leading to inhibition of proliferation and angiogenesis.

Topics: Animals; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Combined Modality Therapy; Curcumin; Electrophoretic Mobility Shift Assay; Gamma Rays; Gene Expression; Humans; Immunohistochemistry; Ki-67 Antigen; Male; Mice; Mice, Nude; Neovascularization, Pathologic; NF-kappa B; Radiation-Sensitizing Agents; Xenograft Model Antitumor Assays

Colorectal cancer remains a leading cause of cancer death worldwide, despite markedly improved response rates to current systemic therapies. Oxaliplatin either alone or incorporated into 5-fluorouracil/leucovorin regimes has resulted in increased survival rates, particularly with regards to metastatic colorectal carcinoma. The chemopreventive polyphenol curcumin, which is currently in clinical trial, has been advocated for use in colorectal cancer either singly or in combination with chemotherapeutic drugs. In this study, the antiproliferative capacity of both compounds was compared in HCEC (normal-derived), HT29 (p53 mutant adenocarcinoma) and HCT116 (p53wt adenocarcinoma) colorectal cell lines to determine whether effects were cell-type specific at pharmacologically achievable doses, and whether the combination resulted in enhanced efficacy. Both oxaliplatin and curcumin displayed marked antiproliferative capacity at therapeutic concentrations in the two tumor cell lines. Order of sensitivity to oxaliplatin was HCT116>HT29>HCEC, whereas order of sensitivity to curcumin was HT29>HCT116>HCEC. HCT116 cells underwent induction of G2/M arrest in response to both oxaliplatin (irreversible) and curcumin (reversible). Apoptosis was induced by both agents, and up to 16-fold induction of p53 protein was observed in response to the combination. Antiproliferative effects in HT29 cells were largely cell cycle independent, and were mediated by induction of apoptosis. Effects were greatly enhanced in both cell lines when agents were combined. This study provides further evidence that curcumin may be of use in therapeutic regimes directed against colorectal cancer, and suggests that in combination with oxaliplatin it may enhance efficacy of the latter in both p53wt and p53 mutant colorectal tumors.

Topics: Annexin A5; Apoptosis; Caspase 3; Caspase 7; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Curcumin; Humans; Organoplatinum Compounds; Oxaliplatin; Tumor Suppressor Protein p53

The role of curcumin (diferuloylmethane), a proapoptotic compound, for the treatment of cancer has been an area of growing interest. Curcumin in its free form is poorly absorbed in the gastrointestinal tract and therefore may be limited in its clinical efficacy. Liposome encapsulation of this compound would allow systemic administration. The current study evaluated the preclinical antitumor activity of liposomal curcumin in colorectal cancer. We also compared the efficacy of liposomal curcumin with oxaliplatin, a standard chemotherapy for this malignancy. In vitro treatment with liposomal curcumin induced a dose-dependent growth inhibition [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt] and apoptosis [poly(ADP-ribose) polymerase] in the two human colorectal cancer cell lines tested (LoVo and Colo205 cells). There was also synergism between liposomal curcumin and oxaliplatin at a ratio of 4:1 in LoVo cells in vitro. In vivo, significant tumor growth inhibition was observed in Colo205 and LoVo xenografts, and the growth inhibition by liposomal curcumin was greater than that for oxaliplatin (P < 0.05) in Colo205 cells. Tumors from animals treated with liposomal curcumin showed an antiangiogenic effect, including attenuation of CD31 (an endothelial marker), vascular endothelial growth factor, and interleukin-8 expression by immunohistochemistry. This study establishes the comparable or greater growth-inhibitory and apoptotic effects of liposomal curcumin with oxaliplatin both in vitro and in vivo in colorectal cancer. We are currently developing liposomal curcumin for introduction into the clinical setting.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Growth Processes; Colorectal Neoplasms; Curcumin; Drug Screening Assays, Antitumor; Drug Synergism; Endocytosis; Female; Humans; Liposomes; Mice; Mice, Nude; Neovascularization, Pathologic; Organoplatinum Compounds; Oxaliplatin; Poly(ADP-ribose) Polymerases; Protein Processing, Post-Translational; Transplantation, Heterologous

(-)-Epigallocatechin-3-gallate (EGCG), one of the main constituents of green tea, has been reported to function as an antioxidant with chemopreventive potential. In contrast, we have recently reported that EGCG enhanced pro-matrix metalloproteinase (MMP)-7 in HT-29 human colon cancer cells via spontaneous superoxide generation. In the present study, we examined the effects of dietary antioxidants on both spontaneous and EGCG-upregulated proMMP-7 production in HT-29 cells. Benzyl isothiocyanate (BITC), curcumin (CUR), gallic acid (GA), and N-acetyl-L-cysteine (NAC) reduced that production, while each alone did not have any effect on spontaneous production. None of the dietary factors suppressed EGCG-induced hydrogen peroxide generation in the media tested, whereas BITC, GA, and NAC inhibited the EGCG-enhanced activator protein (AP)-1 transcription activity by 126%, 77%, and 97%, respectively. Although CUR abolished the EGCG-upregulated MMP-7 mRNA expression, it unexpectedly enhanced the AP-1 activity by 502%, suggesting that this factor may disrupt the MMP-7 mRNA stabilization process. Together, our results indicate that dietary antioxidants modulate EGCG-induced MMP-7 production through different mechanisms.

Topics: Acetylcysteine; Antioxidants; Catechin; Colorectal Neoplasms; Culture Media; Curcumin; Gallic Acid; Genes, Reporter; HT29 Cells; Humans; Hydrogen Peroxide; Isothiocyanates; Luciferases; Matrix Metalloproteinase 7; RNA, Messenger; Transcription Factor AP-1

Multiple studies have indicated that specific COX-2 inhibitors may prevent CRC. However, the long-term use of COX-2 inhibitors is not toxicity-free and may be limited due to its cardiovascular side effects. The present study was carried out to examine the chemopreventive effects of celecoxib and curcumin alone and in combination using the 1,2-dimethylhydrazine (DMH) rat model.. Male rats were injected with DMH and randomly divided into four groups that consumed one of the following diets: (a) AIN-076 control diet; (b) AIN-076/curcumin (0.6%); (c) AIN-076/celecoxib (0.16%), or (d) AIN-076/celecoxib (0.16%) and curcumin (0.6%). Aberrant crypt foci (ACF) were identified by intensive staining with methylene blue in comparison to the surrounding normal crypts.. The average number of ACF per rat colon was 64.2 +/- 3 in the control group, 39 +/- 5 and 47 +/- 10 for the curcumin- and celecoxib-treated group, respectively, and 24.5 +/- 6 in the group that had received both agents.. In vivo, curcumin augments the growth inhibitory effect of celecoxib. This may be clinically important as this dose of celecoxib can be achieved in human serum following standard anti-inflammatory dosing of 100 mg.

Topics: Analysis of Variance; Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Biopsy, Needle; Celecoxib; Cell Proliferation; Cell Survival; Colorectal Neoplasms; Curcumin; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Immunohistochemistry; Male; Probability; Pyrazoles; Random Allocation; Rats; Rats, Inbred F344; Sensitivity and Specificity; Sulfonamides

Studies in vitro and in animal models of colorectal and hepatocellular cancers suggest that curcumin is an effective chemopreventive agent. In this pilot trial, we investigated whether oral administration of curcumin results in concentrations of the agent in normal and malignant human liver tissue, which are sufficient to elicit pharmacological activity. In total, 12 patients with hepatic metastases from colorectal cancer received 450-3600 mg of curcumin daily, for 1 week prior to surgery. Levels of curcumin and its metabolites were measured by HPLC in portal and peripheral blood, bile and liver tissue. Curcumin was poorly available, following oral administration, with low nanomolar levels of the parent compound and its glucuronide and sulphate conjugates found in the peripheral or portal circulation. While curcumin was not found in liver tissue, trace levels of products of its metabolic reduction were detected. In patients who had received curcumin, levels of malondialdehyde-DNA (M(1)G) adduct, which reflect oxidative DNA changes, were not decreased in post-treatment normal and malignant liver tissue when compared to pretreatment samples. The results suggest that doses of curcumin required to furnish hepatic levels sufficient to exert pharmacological activity are probably not feasible in humans.

Topics: Adenocarcinoma; Administration, Oral; Adult; Aged; Anticarcinogenic Agents; Biological Availability; Chromatography, High Pressure Liquid; Colorectal Neoplasms; Curcumin; DNA Adducts; Feasibility Studies; Female; Humans; Liver Neoplasms; Male; Malondialdehyde; Mass Spectrometry; Middle Aged; Pilot Projects; Portal Vein

Curcumin has antioxidative, anti-inflammatory, and chemopreventive activities. To determine whether aging affects the inhibition of colon carcinogenesis by curcumin, young (6 wk), mature (12 mo), and old (22 mo) F344 male rats were fed either AIN-93 containing 0.6% curcumin or AIN-93 control diet. Aberrant crypt foci (ACF) were induced with two weekly s.c. injections of azoxymethane. After an additional 3 mo on the diets, the number, multiplicity, and distribution of ACF were evaluated. Addition of curcumin to the diet reduced the number of ACF by 49% in young rats and by 55% in old rats (P < 0.05). However, interestingly, no reduction of ACF was found in mature rats fed curcumin. Inhibition of large ACF was also affected by age, with the greatest reduction of large ACF occurring in old rats. However, animal age did not significantly alter the effect of dietary curcumin on reduction of cyclooxygenase-2 mRNA expression in the liver or reduction of serum total cholesterol levels. These results indicate that age may play a significant role in the efficacy of chemoprevention of colon cancer by curcumin.

Topics: Aging; Analysis of Variance; Animals; Antineoplastic Agents; Cholesterol; Colon; Colorectal Neoplasms; Curcumin; Enzyme Inhibitors; Gene Expression Regulation, Enzymologic; Immunohistochemistry; Liver; Male; Neoplasms, Experimental; Prostaglandin-Endoperoxide Synthases; Random Allocation; Rats; Rats, Inbred F344

The adenomatous polyposis coli (APC) and mismatch repair (MMR) pathways are both involved in the tumorigenesis of hereditary colorectal cancers. Chemoprevention focuses on the APC pathway in the absence of information concerning MMR targets. This study compared the anticancer effects of sulindac, celecoxib, curcumin, and nifedipine in MMR-deficient cell lines, in order to determine the most appropriate chemopreventive agent for long-term use in patients with hereditary colorectal cancer.. Five human colorectal cell lines (SW480, HCT116, LoVo, SW48, and HCT15) and an endometrial cancer cell line (HEC-1-A) were used for susceptibility testing. Tests included assays for growth inhibition, cell-cycle arrest, and apoptosis.. Sulindac, celecoxib, curcumin, and nifedipine all displayed dose- and time-dependent anti-proliferation activities. Celecoxib was the most effective anti-proliferative agent, and increased the G0/G1 phase proportion in the cell cycle after treatment more significantly than the other agents in all cell lines. Curcumin displayed a more potent apoptosis-inducing activity than the other agents in treated cells.. The tested drugs were effective against colorectal and endometrial cancer cell lines. Celecoxib is more potent with fewer side effects than sulindac. Nifedipine's observed chemopreventive efficacy may complement its known therapeutic application in patients with hypertension.

Topics: Antineoplastic Agents; Apoptosis; Celecoxib; Cell Cycle; Cell Line, Tumor; Chemoprevention; Colorectal Neoplasms; Curcumin; Endometrial Neoplasms; Female; Humans; Nifedipine; Pyrazoles; Sulfonamides; Sulindac

We have investigated the regulation mechanism of chemical stress-induced HSP70 gene expression in human colorectal carcinoma cells (COLO205 and HT29). Our data show that chemical treatments including sodium arsenite and curcumin, induced significant synthesis of HSP70 and its mRNA. The induced HSP70 gene expression appears to be increased at the transcriptional level. The increase in HSP70 gene expression by both chemicals is associated with an increase in HSF binding to HSE and induction of HSF1 di- or trimerization. Phosphorylation and activation of extracellular signal-regulated proteins (ERK1/2) were detected in sodium arsenite-treated COLO205 and HT29 cells, and the free radical scavenger N-acetyl-L-cysteine (NAC) was able to inhibit this ERK1/2 activation and HSP70 gene expression. MAPK blockade by the specific MEK1 inhibitor (PD98059) decreased the ability of sodium arsenite to increase HSP70 gene expression in a dose-dependent manner along with dephosphorylation of ERK1/2 proteins. In contrast to arsenite treatment, activation of ERK1/2 was not detected in curcumin-treated colorectal carcinoma cells, and NAC and PD98059 did not show any inhibitory effect on HSP70 gene expression induced by curcumin. Overexpression of a dominant negative mutant of mitogen-activated protein kinase kinase kinase 1 (MEKK1-DN) prevents arsenite-induced ERK1/2 phosphorylation and HSP70 protein synthesis. These results indicated that the ERK signaling pathway can participate in HSP70 gene expression induced by the prooxidant sodium arsenite, but not by the antioxidant curcumin.

Topics: Acetylcysteine; Arsenites; Blotting, Northern; Blotting, Western; Colorectal Neoplasms; Curcumin; Cyclooxygenase Inhibitors; Dimerization; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Inhibitors; Flavonoids; Free Radical Scavengers; Gene Expression Regulation, Neoplastic; HSP70 Heat-Shock Proteins; Humans; Indomethacin; MAP Kinase Kinase Kinases; Mitogen-Activated Protein Kinases; Phosphorylation; Precipitin Tests; Protein Binding; Time Factors; Transcription, Genetic; Tumor Cells, Cultured