curcumin and Neoplasm-Metastasis

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

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

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

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Biological Availability; Cell Proliferation; Clinical Trials as Topic; Curcumin; Humans; Lung Neoplasms; Neoplasm Invasiveness; Neoplasm Metastasis; Signal Transduction

Integrins are cell-matrix adhesion molecules providing both mechanical engagement of cell to extracellular matrix, and generation of cellular signals that are implicated in cancer malignancies. The concept that integrins play important roles in cell survival, proliferation, motility, differentiation, and ensuring appropriate cell localization, leads to the hypothesis that inhibition of certain integrins would benefit cancer therapy. In lung cancer, integrins αv, α5, β1, β3, and β5 have been shown to augment survival and metastatic potential of cancer cells. This review presents data suggesting integrins as molecular targets for anti-cancer approaches, and the mechanisms through which integrins confer resistance of lung cancer to chemotherapeutics and metastasis. The better understanding of these key molecules may benefit the discovery of anti-cancer drugs and strategies.

Topics: Antineoplastic Agents; Cell Adhesion; Cell Differentiation; Cell Proliferation; Cell Survival; Curcumin; Disease Progression; Extracellular Matrix; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Integrins; Lung Neoplasms; Neoplasm Metastasis; Ouabain; Phloretin; Xanthones

In the last two decades, targeted therapies have enhanced tumor patient care and treatment success, however, metastatic growth still cannot be stopped efficiently and, therefore, mortality rates remain high. Prevention strategies against formation of metastases are the most promising approach we have, however, due to lack of clinical validation studies, they have not yet entered routine clinical care. In order to smooth the way for efficient prevention, further preclinical and large clinical studies are required. In this context, the underlying molecular mechanisms and factors that lead to metastatic growth have to be explored, and potential preventive agents have to be tested. Thereby, special attention has to be paid to natural bioactive compounds which do not exert major adverse effects, like the plant-derived polyphenol Curcumin, which is known to be a powerful antitumor agent. So far, most of the preclinical studies with Curcumin have focused on its effect on inhibiting tumor cell proliferation and invasion, although, it is known that it also inhibits metastatic spread in vivo. This review discusses the preventive potential of this natural compound not only against tumor onset, but also against formation of metastases.

Topics: Apoptosis; Chemoprevention; Curcumin; Feedback, Physiological; Humans; Models, Biological; Neoplasm Metastasis

NF-κB pathway has long been considered as one of the potent prototypical pro-inflammatory signaling pathway and its role in several aspects of human health has been established. Recent studies have suggested that NF-κB activation is the master key in early development and pathobiology of several Cancers. Curcumin is a polyphenolic phytochemical compound with several stablished anti-inflammatory properties and is known to exert its anti-inflammatory effects mostly by interrupting NF-κB signaling pathway at multiple stages. Here we tried to provide a summary of recent finding, focusing on introducing NF-κB signaling pathways and its potential mechanism involved in development of several types of Cancers.

Topics: Anti-Inflammatory Agents; Antineoplastic Agents; Carcinogenesis; Curcumin; Humans; Neoplasm Metastasis; Neoplasms; Neovascularization, Physiologic; NF-kappa B; Signal Transduction

Cancer is the leading cause of death worldwide. Although cancer occurs as a localized disease, its morbidity and mortality rates remain high due to the ability of cancer cells to break-off from the primary tumor and spread to distant organs. Currently, chemotherapy is the main treatment for cancer; however, the increase in proportion of drug-resistant cancer cells and unpleasant side-effects of chemotherapy are still the major challenges in cancer therapy. Curcumin is a natural polyphenol compound and the main bioactive constituent of Indian spice turmeric, widely used in Indian and Chinese medicines. Curcumin has well-known therapeutic actions, including anti-inflammatory, anti-microbial, anti-oxidant and anti-cancer properties. Curcumin induces cancer cell apoptosis through regulating various signaling pathways and arresting tumor cell cycle. Curcumin's therapeutic/ preventative actions on metastatic cancers have not been yet fully understood and studied. The present review explores the potential anti-metastatic mechanisms of curcumin, including inhibition of transcription factors and their signaling pathways (e.g., NF-κB, ApP-1 and STAT3), inflammatory cytokines (e.g., CXCL1, CXCL2, IL-6, IL-8), multiple proteases (e.g., uPA, MMPs), multiple protein kinases (e.g., MAPKs, FAK), regulation of miRNAs (e.g., miR21, miR181b) and heat shock proteins (HLJ1). In addition, possible synergistic actions of combination therapy of curcumin with current chemotherapies are discussed in this review.

Topics: Antineoplastic Agents; Curcumin; Humans; Neoplasm Invasiveness; Neoplasm Metastasis

Despite significant advances in treatment modalities over the last decade, neither the incidence of the disease nor the mortality due to cancer has altered in the last thirty years. Available anti-cancer drugs exhibit limited efficacy, associated with severe side effects, and are also expensive. Thus identification of pharmacological agents that do not have these disadvantages is required. Curcumin, a polyphenolic compound derived from turmeric (Curcumin longa), is one such agent that has been extensively studied over the last three to four decades for its potential anti-inflammatory and/or anti-cancer effects. Curcumin has been found to suppress initiation, progression, and metastasis of a variety of tumors. These anti-cancer effects are predominantly mediated through its negative regulation of various transcription factors, growth factors, inflammatory cytokines, protein kinases, and other oncogenic molecules. It also abrogates proliferation of cancer cells by arresting them at different phases of the cell cycle and/or by inducing their apoptosis. The current review focuses on the diverse molecular targets modulated by curcumin that contribute to its efficacy against various human cancers.

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents, Phytogenic; Cell Proliferation; Curcumin; Humans; Neoplasm Metastasis; Neoplasms

Curcumin (diferuloylmethane) is the most important component of the spice turmeric and is derived from the rhizome of the East Indian plant Curcuma longa. Curcumin has been used extensively in Ayurvedic medicine for centuries, as it is nontoxic and has a variety of therapeutic properties including antioxidant, analgesic, anti-inflammatory, and antiseptic activities. Recently, curcumin has been widely studied for its anticancer properties via its effects on a variety of biological pathways involved in apoptosis, tumor proliferation, chemo- and radiotherapy sensitization, tumor invasion, and metastases. Curcumin can be an effective adjunct in treating solid organ tumors due to its properties of regulating oncogenes like p53, egr-1, c-myc, bcl-XL, etc.; transcription factors like NF-kB, STAT-3, and AP-1; protein kinases like MAPK; and enzymes like COX and LOX. Lung cancer is the most common malignancy worldwide and a leading cause of cancer-related deaths. Seventy-five percent of lung cancer presents at an advanced stage where the existing treatment is not very effective and may result in tremendous patient morbidity. As a result, there is a significant interest in developing adjunctive chemotherapies to augment currently available treatment protocols, which may allow decreased side effects and toxicity without compromising therapeutic efficacy. Curcumin is one such potential candidate, and this review presents an overview of the current in vitro and in vivo studies of curcumin in lung cancer.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Cell Adhesion Molecules; Curcumin; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Genes, Tumor Suppressor; Humans; Lung Neoplasms; Mice; Neoplasm Metastasis; Plant Extracts; Protein Kinases; Radiation-Sensitizing Agents; Rats; Transcription Factors; Tumor Necrosis Factor-alpha

Although safe in most cases, ancient treatments are ignored because neither their active components nor their molecular targets are well defined. This is not the case, however, with curcumin, a yellow-pigment substance and component of turmeric (Curcuma longa), which was identified more than a century ago. Recently, extensive research has addressed the chemotherapeutic potential of this relatively nontoxic-plant-derived polyphenol. Because most cancers are caused by deregulation of as many as 500 different genes, agents that target multiple gene products are needed for prevention and treatment of cancer. In this regard, curcumin has been reported to have immense potentiality for being used in cancer chemotherapy because of its control over the machineries of cell survival, proliferation, invasion, and angiogenesis. The mechanisms implicated are diverse and appear to involve a combination of cell signaling pathways at multiple levels. This review seeks to summarize the unique multifocal signal modulatory properties of the "ancient weapon," curcumin, which may be exploited for successful clinical cancer prevention.

Topics: Animals; Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Proliferation; Curcuma; Curcumin; Gene Expression Regulation, Neoplastic; Humans; Medicine, Ayurvedic; Neoplasm Metastasis; Neoplasms; Rhizome; Signal Transduction

Chemoprevention of malignant tumor growth is a novel and potentially powerful approach for tumor therapy. Recent in vitro and in vivo investigations provide increasing evidence that naturally occurring substances may exhibit significant chemopreventive activities. To this regard, the spice Curcumin, widely used in Indian cuisine, has been identified to show considerable anti-tumor effects. Most interestingly, numerous studies have not shown toxic side effects of this substance. Curcumin induces tumor cell apoptosis along with a reduction of tumor cell invasion and metastasis. Recent molecular studies provide evidence that Curcumin acts via a control of the NFkappaB pathway exerting most of the various modulating and moderating effects on malignant cells. Along with these in vitro studies, ex vivo and first clinical investigations confirm the anti-tumor effects of Curcumin, either as an isolated chemoprevention substance or in combination with chemotherapeutic agents as supportive measure reducing pharmaceutical resistance of tumor cells to certain chemotherapeutics. Despite our increasing knowledge on this interesting substance there still remain many unknown effects that deserve intense investigation.

Topics: Anticarcinogenic Agents; Apoptosis; Cell Cycle; Cell Proliferation; Chemoprevention; Curcuma; Curcumin; Humans; MicroRNAs; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms

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

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

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

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

Curcumin was found to be cytotoxic in nature to a wide variety of tumor cell lines of different tissue origin. The action of curcumin is dependent on with the cell type, the concentration of curcumin (IC50: 2-40 microg/mL), and the time of the treatment. The major mechanism by which curcumin induces cytotoxicity is the induction of apoptosis. Curcumin decreased the expression of antiapoptotic members of the Bcl-2 family and elevated the expression of p53, Bax, procaspases 3, 8, and 9. Curcumin prevents the entry of nuclear factor KB (NF-KB) into the nucleus there by decreasing the expression of cell cycle regulatory proteins and survival factors such as Bcl-2 and survivin. Curcumin arrested the cell cycle by preventing the expression of cyclin D1, cdk-1 and cdc-25. Curcumin inhibited the growth of transplantable tumors in different animal models and increased the life span of tumor-harboring animals. Curcumin inhibits metastasis of tumor cells as shown in in vitro as well as in vivo models, and the possible mechanism is the inhibition of matrix metalloproteases. Curcumin was found to suppress the expression of cyclooxygenase-2, vascular endothelial growth factor, and intercellular adhesion molecule- and elevated the expression of antimetastatic proteins, the tissue inhibitor of metalloproteases-2, nonmetastatic gene 23, and Ecadherin. These results indicate that curcumin acts at various stages of tumor cell progression.

Topics: Animals; Antineoplastic Agents, Phytogenic; Curcumin; Humans; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms

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

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

Despite the fact that androgen deprivation therapy (ADT) can effectively reduce prostate cancer (PCa) size, its effect on PCa metastasis remains unclear. We examined the existing data on PCa patients treated with ADT plus anti-androgens to analyze ADT effects on primary tumor size, prostate-specific antigen (PSA) values, and metastatic incidence. We found that the current ADT with anti-androgens might lead to primary tumor reduction, with PSA decreased yet metastases increased in some PCa patients. Using in vitro and in vivo metastasis models with four human PCa cell lines, we evaluated the effects of the currently used anti-androgens, Casodex/bicalutamide and MDV3100/enzalutamide, and the newly developed anti-AR compounds, ASC-J9® and cryptotanshinone, on PCa cell growth and invasion. In vitro results showed that 10 μm Casodex or MDV3100 treatments suppressed PCa cell growth and reduced PSA level yet significantly enhanced PCa cell invasion. In vivo mice studies using an orthotopic xenograft mouse model also confirmed these results. In contrast, ASC-J9® led to suppressed PCa cell growth and cell invasion in in vitro and in vivo models. Mechanism dissection indicated these Casodex/MDV3100 treatments enhanced the TGF-β1/Smad3/MMP9 pathway, but ASC-J9® and cryptotanshinone showed promising anti-invasion effects via down-regulation of MMP9 expression. These findings suggest the potential risks of using anti-androgens and provide a potential new therapy using ASC-J9® to battle PCa metastasis at the castration-resistant stage.

Topics: Androgen Receptor Antagonists; Androgens; Anilides; Animals; Benzamides; Cell Line, Tumor; Curcumin; Down-Regulation; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Male; Matrix Metalloproteinase 9; Mice; Mice, Nude; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Proteins; Neoplasm Transplantation; Neoplasms, Experimental; Nitriles; Phenylthiohydantoin; Prostate-Specific Antigen; Prostatic Neoplasms; Smad3 Protein; Tosyl Compounds; Transforming Growth Factor beta1; Transplantation, Heterologous; Xenograft Model Antitumor Assays

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

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

Breast cancer is the most common cancer in women globally, and diagnosing it early and finding potential drug candidates against multi-drug resistant metastatic breast cancers provide the possibilities of better treatment and extending life.. The current study aimed to evaluate the synergistic anti-metastatic activity of Curcumin (Cur) and Paclitaxel (Pacli) individually, the combination of Curcumin-Paclitaxel (CP), and also in conjugation with gold nanoparticles (AuNP-Curcumin (Au-C), AuNP-Paclitaxel (Au-P), and AuNP-Curcumin-Paclitaxel (Au-CP)) in various in vitro and in vivo models.. The results from combination treatments of CP and Au-CP demonstrated excellent synergistic cytotoxic effects in triple-negative breast cancer cell lines (MDA MB 231 and 4T1) in in vitro and in vivo mouse models. Detailed mechanistic studies were performed that reveal that the anti-cancer effects were associated with the downregulation of the expression of VEGF, CYCLIN-D1, and STAT-3 genes and upregulation of the apoptotic Caspase-9 gene. The group of mice that received CP combination therapy (with and without gold nanoparticles) showed a significant reduction in the size of tumor when compared to the Pacli alone treatment and control groups.. Together, the results suggest that the delivery of gold conjugated Au-CP formulations may help in modulating the outcomes of chemotherapy. The present study is well supported with observations from cell-based assays, molecular and histopathological analyses.

Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinogenesis; Cell Line; Cell Line, Tumor; Curcumin; Drug Resistance, Multiple; Female; Gold; HEK293 Cells; Humans; Metal Nanoparticles; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Paclitaxel; Triple Negative Breast Neoplasms

Topics: Apoptosis; Cell Adhesion; Cell Cycle; Cell Line, Tumor; Cell Movement; Cell Proliferation; Clone Cells; Curcumin; Human Umbilical Vein Endothelial Cells; Humans; Integrins; Light; Male; Neoplasm Metastasis; Prostatic Neoplasms

Systemic chemotherapy is still the primary treatment for advanced-stage nasopharyngeal carcinoma (NPC), but only limited therapeutic success has been achieved in the past decade because of drug resistance and systemic toxicity. Curcumin (Cur) is an effective alternative to chemotherapeutics because it showed remarkable therapeutic potential in the treatment of NPC. However, lack of tissue specificity and poor penetration in solid tumors are the major obstacles to effective therapy. Therefore, in this work, a self-assembled sub-30 nm therapeutic lipid nanoparticle loaded with Cur, named as Cur@α-NTP-LN, was constructed, specifically targeting scavenger receptor class B member 1 (SR-B1) and enhancing its therapeutic effects on NPC in vivo. Our results showed that Cur@α-NTP-LNs were effective and superior to free Cur on NPC cell-specific targeting, suppressing cell proliferation and inducing cell apoptosis. In vivo and ex vivo optical imaging revealed that Cur@α-NTP-LNs exerted high targeting efficiency, specifically accumulating in NPC xenograft tumors and delivering Cur into the tumor center after systemic administration. Furthermore, Cur@α-NTP-LNs exhibited a remarkable inhibitory effect on the growth of NPC subcutaneous tumors, with over 71 and 47% inhibition compared to Cur- and α-NTP-LNs-treated groups, respectively. In addition, Cur@α-NTP-LNs almost blocked NPC metastasis in a lung metastasis model of NPC and significantly improved the survival rate. Thus, the sub-30 nm Cur@α-NTP-LNs enhanced the solubility of Cur and demonstrated the ability of targeted Cur delivery into the center of the solid NPC tumor, performing synergistic inhibitory effects on the growth of NPC tumor and its metastasis with high efficiency.

Topics: Administration, Cutaneous; Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Curcumin; Drug Carriers; Drug Delivery Systems; Humans; Liposomes; Lung Neoplasms; Mice; Nanoparticles; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Neoplasm Metastasis; Particle Size; Peptides; Solubility

This study tested the hypothesis that heparanase (HPSE) is related to tumor metastasis and curcumin (CCM) inhibits tumor metastasis by down-regulating HPSE expression. MTT, Transwell assays, and RT-PCR were used to study the effects of CCM on the migration and invasion of CT26 cells and the expression of HPSE. CT26 cells were transfected with lentivirus to establish HPSE-overexpressing cells (OE) and corresponding negative control cells (NC). Signal pathways involved in down-regulating the expression of HPSE and inhibiting the migration and invasion of CT26 cells by CCM were screened by the liquid crystal chip. HPSE promoted CT26 cells migration and invasion, and CCM inhibited the proliferation and metastasis of CT26 cells. The results of RT-PCR indicated that CCM down-regulated HPSE expression. Liquid phase microarray showed that CCM inhibited the phosphorylation of P38 and STAT5 in CT26 cells and NC cells. In contrast, the inhibitory function of CCM was markedly enhanced when HPSE was overexpressed (P < 0.05). In short, HPSE is closely related to metastasis of colon cancer cells. CCM inhibits colon cancer cell migration and invasion by inhibiting HPSE expression, which may be related to P38 MAPK and JAK/STAT5 signal pathways.

Topics: Cell Line, Tumor; Colonic Neoplasms; Curcumin; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Glucuronidase; Humans; MAP Kinase Signaling System; Neoplasm Metastasis; Neoplasm Proteins

The cytotoxic and apoptotic effects of turmeric (Curcuma longa) on colon cancer have been well documented but specific structural modifications of curcumin have been shown to possess greater growth-suppressive potential on colon cancer than curcumin. Therefore, the aim of this study is to identify the anti-cancer properties of curcumin analogue-MS13, a diarylpentanoid on the cytotoxicity, anti-proliferative and apoptotic activity of primary (SW480) and metastatic (SW620) human colon cancer cells. A cell viability assay showed that MS13 has greater cytotoxicity effect on SW480 (EC

Topics: Apoptosis; Caspase 3; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Curcumin; Cytotoxins; Humans; Neoplasm Metastasis; Proto-Oncogene Proteins c-bcl-2

Curcumin is a natural phytochemical polyphenol with significant anti-cancer effects and negligible side effects. In this study, the therapeutic capacity of nanomicellar-curcumin for treating lung metastasis was evaluated in an immunocompetent mouse model of metastatic melanoma.. Two doses of nanomicellar-curcumin (i.e. 10 and 20 μM) were used to induce cytotoxicity in 3 melanoma cell lines. A total of 60 mice were allocated to 20 mice in each of three groups (10 for survival and 10 for assays). Groups were no treatment control, PBS control, nanomicellar-curcumin 20 mg/kg IP 4 times a week, for three weeks). Immunohistochemistry, TUNEL assay, and Western blots were used on lung samples.. Nanomicellar-curcumin inhibited the in vitro growth of B16 F10 melanoma cells at 20 μM over 72 h. In vivo, 20 mg/kg nanomicellar-curcumin injected IP, delayed tumor cell growth and significantly extended mouse survival rate. Tumor infiltration of regulatory T cells and angiogenesis were reduced, while IFN-γ and CXCL10 were increased.. Nanomicellar-curcumin can inhibit lung metastasis and growing melanoma via activation of apoptosis, activated T cells and inhibition of angiogenesis, tumor growth and regulatory T cells.

Topics: Animals; Apoptosis; Cell Proliferation; Cell Survival; Curcumin; Disease Models, Animal; Humans; Lung Neoplasms; Melanoma, Experimental; Neoplasm Metastasis; Neovascularization, Pathologic; T-Lymphocytes, Regulatory

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

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

Fascin is an actin-binding protein and highly expressed in ovarian cancer cells. It is associated with metastasis of cancer and may be a useful prognostic factor. Anticancer activity of curcumin is related to its effect on several signaling mechanisms. Although there have been many reports regarding the anticancer properties of curcumin, its inhibitory effects on migration and invasion of ovarian cancer cells, particularly in the context of fascin expression, have not been reported. The purpose of this study was to investigate the effect of curcumin on fascin expression in ovarian cancer cells and to propose a possible mechanism for the anticancer activity of curcumin through reduced fascin expression.. SKOV3, human epithelial ovary cancer cell line, was cultured with curcumin at various dose and duration. The fascin was quantified using cell viability test and Western blot. To determine the effect of curcumin on the upstream pathway of fascin expression, the signal transducer and activator of transcription 3 (STAT3) was analyzed by sandwich-ELISA. Attachment assay, migration assay and invasion assay were analyzed to approve the change of cellular invasiveness of ovary cancer after curcumin. To determine the morphological changes of ovarian cancer cells by curcumin, immunofluorescence was performed.. MTS assays showed that cell viability was different at various concentration of curcumin, and as concentration increased, cell viability tended to decrease. Curcumin appears to suppress fascin expression, even with a minimal concentration and short exposure time. Also, curcumin may suppress fascin expression in ovarian cancer cells through STAT3 downregulation. The attachment assay, migration assay and invasion assay of the ovarian cancer cells exhibited a statistically significant decrease. Immunofluorescence revealed a change of cell shape from a typical form of uninfluenced cells to a more polygonal appearance, with a significant reduction in filopodia formation.. Curcumin reduces fascin expression through JAK/STAT3 pathway inhibition, which interferes with the cellular interactions essential for the metastasis and recurrence of ovarian cancer cells. Higher curcumin concentrations and longer exposure times concomitantly decreased fascin expression.

Topics: Carrier Proteins; Curcumin; Female; Humans; Janus Kinases; Microfilament Proteins; Neoplasm Metastasis; Neoplasm Recurrence, Local; Ovarian Neoplasms; Signal Transduction; STAT3 Transcription Factor

Cancer is one of the most deadly diseases spreading all over the world and a major cause of fear in the society. Colon cancer is the 4th most common cancer causing death in both male and female equally, mainly caused due to the improper diet plans, consumption of the red meat and lack of exercise. Although the design of the chemotherapeutic drugs is well advanced, many of them developed resistance towards the cancer cells. The major reason behind the drug resistance in the colon cancer cells is due to the action exhibited by P-gp, which belongs to a member of ABC transporter family. P-glycoprotein (P-gp) effluxes the drug from its entry into the cancer cells, by treating it as a foreign body and hence decreases the therapeutic concentration of chemotherapeutic drugs inside the cancer cells. For overcoming this scenario, we posit the use of the curcumin (as a flavonoid) along with the lipid and the chemotherapeutic drug to provide an effective therapy and to overcome the possible issues associated with the failure in the therapy. Curcumin possesses dual mode of actions as a chemosensitizing agent and also as a chemotherapeutic drug. It generally acts as a chemosensitizer which can alter or inhibit the efflux pump exhibited by P-gp and provide a pathway for the entry of the chemotherapeutic drug into the cancer cells. Lipids have the potential to overcome the Multidrug resistance (MDR) and related issues; in addition, lipids are used for targeting colon cancer cells and also can act during the metastatic condition of the cancer which is hypothesised to be proven by using various studies. If our hypothesis is proven, the use of curcumin with lipids and the chemotherapeutic drug in a novel combination will reduces the majority of the issues related to the multidrug resistance, the recurrence and the spread of cancer could be overcome in a safe and effective manner.

Topics: Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cell Line, Tumor; Colonic Neoplasms; Curcumin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Flavonoids; Fluorouracil; Humans; Lipids; Lymphatic System; Neoplasm Metastasis; Neoplasm Recurrence, Local

UNCI 19 expression has been reported to be significantly higher in hepatic cancer cells (HCC). However, the clinical significance of modulating UNC119 expression in HCC is not well understood. The study described here aimed to explore the potential of curcumin in modulation of UNC119 expression in HCC by assessment with quantitative real-time PCR, western blot, and immune-histochemical analyses in HCC cell lines and tissues. The biological functions of UNC119 in the proliferation, growth, and cycle of tumor cells were analyzed both in vitro and in vivo. UNC119 expression was upregulated in HCC cell lines and tissues as indicated by comparison with normal liver cells and tissues. Cellular function assays showed that higher levels of UNC119 not only promoted proliferation but also enhanced HCC cell migration and invasion. UNC119 promoted progression of the cell cycle and significantly promoted HCC cell growth through the Wnt/β-catenin signal pathway, and enhanced tumor migration and invasion by the TGF-β/EMT pathway. Curcumin efficiently inhibited HCC cell proliferation by blocking the Wnt/β-catenin pathway and inhabited migration and invasion by blocking the TGF-p/EMT signal pathway. Curcumin not only was beneficial for tumor remission but also contributed to the long-term survival of HCC-bearing mice. UNC119 was significantly upregulated and promoted cell growth in hepatic cancer cells and tissues by the Wnt/β-catenin signal pathway and migration by TGF-β/EMT signal pathway. Curcumin treatment inhibited cell proliferation, growth, migration, and invasion by inhibition of those pathways.

Topics: Adaptor Proteins, Signal Transducing; Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Curcumin; Female; Hep G2 Cells; Humans; Mice; Mice, Inbred BALB C; Neoplasm Invasiveness; Neoplasm Metastasis; Specific Pathogen-Free Organisms

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

Chronic inflammation is closely related to the development, deterioration, and metastasis of tumors. Recently, many studies have shown that down-regulating the expression of inflammation by blocking nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) pathways could significantly inhibit tumor growth and metastasis. The combined application of curcumin (CUR) and celecoxib (CXB) has been proven to exert a synergistic antitumor effect via inhibiting the activation of NF-κB and STAT3. TAT-NBD (TN) peptide, a fusion peptide of NF-κB essential modulator (NEMO)-binding domain peptide (NBD) and cell-penetrating peptide (TAT), can selectively block NF-κB activating pathway resulting in tumor growth inhibition. In the present study, a novel TN-modified liposome coloading both CXB and CUR (TN-CCLP) at a synergistic ratio was first constructed with the property of synchronous release, then hyaluronic acid (HA) as CD44 targeting moiety was coated on the surface of the cationic liposome via electrostatic interaction to prepare the anionic HA/TN-CCLP. In vitro results of cytotoxicity, macrophage migration inhibition, and anti-inflammation efficacy revealed that TN-CCLP and HA/TN-CCLP were significantly superior to TN-LP and CCLP, while TN-CCLP exhibited better effects than HA/TN-CCLP due to higher cellular uptake ability. Different from in vitro data, after systematically treating 4T1 breast tumor-bearing mice, HA/TN-CCLP exerted the most striking effects on anti-inflammation, inhibition of macrophage recruitment, and antitumor because of the longest circulation time and maximum tumor accumulation. In particular, HA/TN-CCLP could availably block the lung metastasis of breast cancer. Taken together, the novel CD44 targeted TN-CCLP exhibited the potential for inhibiting tumor development and metastasis through improving inflammatory infiltration of tumor tissue.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Celecoxib; Cell Line, Tumor; Cell Movement; Cell-Penetrating Peptides; Curcumin; Drug Liberation; Drug Synergism; Drug Therapy, Combination; Female; Heterografts; Humans; Hyaluronan Receptors; Hyaluronic Acid; Inflammatory Breast Neoplasms; Liposomes; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Metastasis; NF-kappa B; Treatment Outcome; Tumor Burden

Wilms' tumor (WT) is the most common kidney tumor of children. The transformation suppressor gene RECK, which codes membrane-anchored glycoprotein, frequently downregulates multiple matrix metalloproteinases in tumors. And curcumin, which is a polyphenlic compound separated from turmeric, has antitumor effects on various cancers. However, the correlation of WT, RECK and curcumin is still unrevealed. In this study, we evaluated that the methylation degree of RECK was much higher in WT than in adjacent non-tumor tissues. And RECK methylation was closely associated with tumor metastasis in WT patients. After curcumin treatment, the level of RECK methylation was decreased significantly. And the expression of MMP2 and MMP9 was reduced consequently. Moreover, the proliferation, invasion and migration ability of WT cells were suppressed after curcumin treatment. Meanwhile, the apoptosis rate of WT cells was increased simultaneously. In nude mice model, curcumin restrained ability of tumorigenicity and promoted apoptosis of WT cells. Together, our results suggest that the RECK methylation can serve as a prognostic biomarker of WT. Moreover, curcumin could inhibit RECK methylation, thereby abates the expression of MMPs, and suppresses the tumor progression and metastasis of WT.

Topics: Animals; Apoptosis; Biomarkers, Tumor; Carcinogenesis; Cell Movement; Cell Proliferation; Child, Preschool; Curcumin; DNA Methylation; Down-Regulation; Female; GPI-Linked Proteins; Humans; Kidney Neoplasms; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Nude; Neoplasm Metastasis; Wilms Tumor

Curcumin attracted attention due to its promising anti-cancer properties and safety performance. However, its poor aqueous solubility and low bioavailability have to be overcome before it goes into clinic use. Here, porous composite particles are prepared by loading curcumin into mesoporous material SBA-15, and its therapeutic effect on lung cancer via inhalation administration have also been evaluated. The inclusion of curcumin in host material SBA-15 was confirmed by the reduced surface area and pore diameter of the composite material, and the aerodynamic performance of the composite material was investigated by FT-4 and NGI. Phagocytosis experiments on RAW264.7, the toxicity of material extracts on BEAS-2B cells, and the haemolysis experiments showed that the mesoporous materials had good biocompatibility at 10-400 μg/mL. The B16F10 melanoma metastatic lung mouse model was used to investigate the therapeutic effect of lung cancer after inhalable administration. It was found that the body weight of the curcumin composite particle-administered group decreased more slowly and the lung disease developed slower than the curcumin crude drug group, indicating that the composite particles has a certain inhibitory effect on tumours.

Topics: Administration, Inhalation; Animals; Biological Availability; Cell Culture Techniques; Curcumin; Drug Carriers; Humans; Lung Neoplasms; Mice; Mice, Inbred C57BL; Models, Animal; Neoplasm Metastasis; Particle Size; Phagocytosis; RAW 264.7 Cells; Silicon Dioxide; Solubility

Surgical removal of the primary tumor is a common practice in breast cancer treatment. However, postsurgical metastasis poses an immense setback in cancer therapy. Considering that 90% of cancer-related deaths are due to metastasis, antimetastatic therapeutic strategies that can target disseminating tumor cells in the circulation before they can form secondary tumors hold preclinical and clinical potential for cancer patients. Our current work uses a liposomal formulation functionalized with the adhesion receptor E-selectin and the apoptosis-inducing ligand TNF (tumor necrosis factor)-related apoptosis-inducing ligand (TRAIL) to reduce metastasis following tumor resection in an aggressive triple-negative breast cancer (TNBC) mouse model. We demonstrate that minimal administration of E-selectin-TRAIL liposomes can target metastasis in a TNBC model, with primary tumor resection to mimic clinical settings. Our study indicates that TRAIL liposomes, alone or in combination with existing clinically approved therapies, may neutralize distant metastasis of a broad range of tumor types systemically.

Topics: Animals; Apoptosis; Aspirin; Cell Line, Tumor; Cell Proliferation; Curcumin; Dioxolanes; E-Selectin; Female; Humans; Leukocytes; Liposomes; Mammary Glands, Animal; Mice; Neoplasm Metastasis; Neoplasms, Experimental; TNF-Related Apoptosis-Inducing Ligand; Triple Negative Breast Neoplasms

The combination of traditional Chinese medicines can improve the efficacy of cancer treatment. Furthermore, the combination of the traditional Chinese medicine curcuma zedoary and kelp was used to enhance the effect of the dissipation of blood stasis in pediatrics during the Song Dynasty. Curcumenol and laminarin, the main components of curcuma zedoary and kelp, are also reported to have a wide range of biological activities. Therefore, we hypothesize that the combination of curcuma zedoary and kelp may prevent the development of cancer. The aim of this research was to confirm whether a combination of curcuma zedoary and kelp could inhibit the proliferation and metastasis of hepatoma cells and consequently improve prognosis. In this study, we firstly found in H22-bearing mice that the combination of curcuma zedoary and kelp inhibited tumor growth and the expression of metastasis-related proteins (MMPs, VEGF, pAkt, pERK1/2). Meanwhile, the decreased cystathionine beta synthase (CBS, an endogenous hydrogen sulfide (H2S) synthetase) level was also observed in H22-bearing mice admistrated with the combination of curcuma zedoary and kelp. It was also observed that the combination of curcumenol and laminarin inhibited the proliferation, migration and invasion in human hepatoma HepG2 cells. Furthermore, we investigated the potential inhibiting mechanism of the combination of curcumenol and laminarin on HepG2 cell proliferation and metastasis. Our previous research showed that a CBS/H2S system was vital for maintaining the proliferation in hepatoma cells. Here, we found that the levels of pSTAT3 and BCL-2 were decreased in CBS knockdown HepG2 cells and the combination of curcumenol and laminarin significantly decreased the H2S level in a dose-dependent manner and down-regulated the levels of pSTAT3 and BCL-2 in HepG2 cells. Angiogenesis, positively regulated by the vascular endothelial growth factor (VEGF), is essential for human cancer metastasis. In the present study, we found that the combination of curcumenol and laminarin could significantly down-regulate the expression levels of VEGF and its downstream key genes pAkt and pERK1/2. Furthermore, previous research showed that hydrogen sulfide could stimulate angiogenesis. Here, we also observed the reduction of the VEGF, Akt, pAkt, ERK1/2 and pERK1/2 proteins levels and the inhibition of proliferation and metastasis in CBS knockdown HepG2 cells. Moreover, exogenous H2S rescued the cytological results caused by

Topics: Animals; Cell Line, Tumor; Cell Movement; Cell Proliferation; Curcuma; Drugs, Chinese Herbal; Female; Humans; Hydrogen Sulfide; Kelp; Liver Neoplasms; Male; Mice; Neoplasm Metastasis; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; STAT3 Transcription Factor; Vascular Endothelial Growth Factor A

Topics: Animals; Antineoplastic Agents; Curcuma; Female; Genes, fos; Genes, jun; Lung Neoplasms; Mammary Neoplasms, Experimental; Matrix Metalloproteinase 9; Mice; Mice, Transgenic; Neoplasm Metastasis; Plant Extracts; Plant Roots; Receptors, CCR7

Hepatocellular carcinoma (HCC) has poor prognosis due to the advanced disease stages by the time it is diagnosed, high recurrence rates and metastasis. In the present study, we investigated the effects of metformin (a safe anti-diabetic drug) and curcumin (a turmeric polyphenol extracted from rhizome of Curcuma longa Linn.) on proliferation, apoptosis, invasion, metastasis, and angiogenesis of HCC in vitro and in vivo. It was found that co-treatment of metformin and curcumin could not only induce tumor cells into apoptosis through activating the mitochondria pathways, but also suppress the invasion, metastasis of HCC cells and angiogenesis of HUVECs. These effects were associated with downregulation of the expression of MMP2/9, VEGF, and VEGFR-2, up-regulation of PTEN, P53 and suppression of PI3K/Akt/mTOR/NF-κB and EGFR/STAT3 signaling. Co-administration of metformin and curcumin significantly inhibited HCC tumor growth than administration with metformin or curcumin alone in a xenograft mouse model. Thus, metformin and curcumin in combination showed a better anti-tumor effects in hepatoma cells than either metformin or curcumin presence alone and might represent an effective therapeutic strategy for HCC treatment.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Cell Line; Cell Proliferation; Cells, Cultured; Curcumin; Female; Hep G2 Cells; Humans; Liver Neoplasms; Metformin; Mice, Inbred BALB C; Mice, Nude; Neoplasm Metastasis; Neovascularization, Pathologic; Signal Transduction; Tumor Burden; Xenograft Model Antitumor Assays

Due to the high rate of drug resistance among malignant melanoma cases, it seems necessary to introduce an efficient pharmaceutical approach to melanoma treatment. For this purpose, Curcumin (Cur) and Chrysin (Chr), two natural anti-cancers, were co-encapsulated in PLGA-PEG nanoparticles (NPs), characterized by DLS, FTIR and FE-SEM and investigated for their effects on MMPs, TIMPs and TERT genes expression in C57B16 mice bearing B16F10 melanoma tumours. The results showed that the expression of MMP-9, MMP-2 and TERT genes were significantly decreased in all treated groups compared to the control. This reduction had the highest amount in CurChr NPs group and then CurChr group for each three genes. Likewise, the expression of TIMP-1 and TIMP-2 genes was significantly increased in all treated groups, compared to the control. Combination groups showed the highest rise in expression of these two genes and the observed increase was greater in nano groups. Moreover, the highest melanoma tumour growth inhibition was detected for CurChr NPs, followed by CurChr = Cur NPs > Cur > Chr NP > Chr. Overall, it is speculated that the nano-combination of Cur and Chr into polymeric NPs with a one-step fabricated co-delivery system may be a promising and convenient approach to improve their efficiency in melanoma cancer therapy.

Topics: Animals; Capsules; Cell Proliferation; Curcumin; Disease Models, Animal; Disease Progression; Drug Carriers; Flavonoids; Gene Expression Regulation, Neoplastic; Male; Matrix Metalloproteinases; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Nanoparticles; Neoplasm Metastasis; Polyethylene Glycols; Polylactic Acid-Polyglycolic Acid Copolymer; Telomerase; Tissue Inhibitor of Metalloproteinases

Demethoxycurcumin (DMC), one of the curcuminoids present in turmeric, has been shown to induce cell death in many human cancer cell lines, however, there has not been any investigation on whether DMC inhibits metastatic activity in human cervical cancer cells in vitro. In the present study, DMC at 2.5-15 μM decreased cell number, thus, we used IC. The wound healing, migration, invasion, zymography, and western blotting assays were used to investigate the effects of DMC on HeLa cells.. The wound healing assay was used to show that DMC suppressed cell movement of HeLa cells. Furthermore, the trans-well chamber assay was used to show that DMC suppressed HeLa cell migration and invasion. Gelatin zymography assay did not show any significant effects of DMC on the gelatinolytic activity (MMP-2 and -9) in conditioned media of HeLa cells treated by DMC. Western blotting showed that DMC significantly reduced protein levels of GRB2, MMP-2, ERK1/2, N-cadherin and Ras but increased the levels of E-cadherin and NF-κB in HeLa cells. Confocal laser microscopy indicated that DMC increased NF-κB in HeLa cells confirming the results from Western blotting.. DMC may be used as a novel anti-metastatic agent for the treatment of human cervical cancer in the future.

Topics: Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Cell Movement; Culture Media, Conditioned; Curcumin; Diarylheptanoids; Drug Screening Assays, Antitumor; Female; Gene Expression Regulation, Neoplastic; HeLa Cells; Humans; Matrix Metalloproteinases; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Proteins; NF-kappa B

Tumor metastasis is the leading cause of cancer death; due to the progress made in the elucidation of the mechanism of cancer cell metastasis, there is hope for patients with severe stages of cancer. Curcumin, as a novel anti-cancer drug, has been applied in cancer therapy; however, the toxicity of curcumin hinders its application. Herein, we constructed a novel derivative, WZ35, and evaluated its metastatic inhibition properties in vitro and in vivo. CCK-8 assay was performed to evaluate the tumor suppressive activity of WZ35. Cell apoptosis was detected by flow cytometry analysis. Transwell cell migration assay and RTCA were used to detect cell migration in mock and WZ35-treated cells. Western blotting was performed to analyze molecular alteration with different treatments. In this study, we found that curcumin and its derivative WZ35 could dramatically suppress proliferation, invasion, and migration of the hepatocellular HCCLM3, HepG2, and Huh7 cancer cells. Moreover, the cancer cell metastatic markers MMP-2, MMP-9, and N-cadherin were decreased, and E-cadherin was up-regulated. In addition, our data show that WZ35 promotes ROS-dependent JNK activation that is essential for WZ35-caused cell metastasis suppression. Moreover, the NAC and JNK inhibitor SP600125 could dramatically reverse WZ35-caused MMP-2, MMP-9, and N-cadherin reduction and E-cadherin up-regulation. We have also found that WZ35 exhibits powerful anti-metastasis activity of HCCLM3 in vivo. In conclusion, our data indicated that WZ35 could be a candidate for the treatment of metastatic liver cancer patients.

Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Hepatocellular; Cell Movement; Curcumin; Female; Humans; Liver Neoplasms; MAP Kinase Kinase 4; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Reactive Oxygen Species

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

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

Curcumin has been revealed to inhibit liver cancer, however, no studies have reported that the mechanism of curcumin's action on liver cancer is related to damage-associated molecular pattern (DAMP) molecules heat shock protein 70 (HSP70) and the toll-like receptor 4 (TLR4) signaling. This study aimed to investigate whether the activation of TLR4 signaling by HSP70 could be inhibited by curcumin, thus investigating the possible mechanism of curcumin in the inhibition of liver cancer. Western blotting was used to evaluate the expression of the HSP70 and TLR4 in HepG2 cells and ELISA was used to detect the concentration of HSP70 in cell culture medium. A thermal tolerance HepG2 (HepG2TT) cell model was established to simulate HSP70 accumulation in the microenvironment. A certain concentration of curcumin was co-cultured with HepG2 and HepG2TT cells to observe the changes of HSP70 and TLR4. Our results revealed that heat stress significantly increased the expression of extracellular HSP70 (eHSP70) and TLR4 (P<0.01), but significantly reduced the expression of intracellular HSP70 (P<0.01). Curcumin inhibited proliferation, invasion, and metastasis of HepG2 cells, caused cells to remain in the DNA S phase, promoted apoptosis, and significantly reduced intracellular HSP70, eHSP70 and TLR4 levels of HepG2TT cells. Following the removal of curcumin, eHSP70 increased again. In summary, our results demonstrated that the antitumor effect of curcumin was related to the inhibition HSP70-TLR4 signaling.

Topics: Alarmins; Antineoplastic Agents; Apoptosis; Cell Proliferation; Curcumin; Hep G2 Cells; HSP72 Heat-Shock Proteins; Humans; Liver Neoplasms; Neoplasm Invasiveness; Neoplasm Metastasis; S Phase; Toll-Like Receptor 4; Tumor Microenvironment

Bisdemethoxycurcumin (BDMC) exhibits biological activities including anticancer and anti-metastasis in human cancer cell lines, but there is no available information to show whether BDMC suppresses cell migration and invasion of human cervical cancer cells.. Wound-healing, migration, invasion, zymography, and western blotting assays were used to investigate the effects of BDMC on HeLa cells in vitro.. BDMC reduced the total viable cell number in a dose-dependent manner. The wound-healing assay show BDMC suppressed the movement of HeLa cells. Furthermore, the trans-well chamber assays showed that BDMC suppressed the cell migration and invasion. Gelatin zymograph assay showed that BDMC did not inhibit matrix metalloproteinase-2 (MMP-2) and -9 activities in vitro. However, western blotting assay showed that BDMC significantly reduced protein levels of growth factor receptor-bound protein 2 (GRB2), Ras homolog gene family, member A (Rho A), urokinase-type plasminogen activator (uPA), RAS, MMP-2, and N-cadherin but increased those of phosphor-extracellular-signal related kinase (p-ERK1/2), E-cadherin and nuclear factor-ĸB (NF-ĸB) in HeLa cells. Confocal laser microscopy assay was used to further confirm BDMC increased NF-ĸB when compared to controls.. BDMC may have potential as a novel anti-metastasis agent for the treatment of human cervical cancer.

Topics: Blotting, Western; Curcumin; Diarylheptanoids; Dose-Response Relationship, Drug; Electrophoresis, Polyacrylamide Gel; Female; HeLa Cells; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Microscopy, Confocal; Neoplasm Invasiveness; Neoplasm Metastasis; NF-kappa B; Uterine Cervical Neoplasms

Curcumin is widely considered beneficial to human health, but insolubility and instability greatly hamper reproducible exploitation of the advantageous traits. Here we report on the development, characterization and evaluation of a curcumin-loaded nanoemulsion (CUR-NEM) that is highly effective in preventing post-surgery tumor reincidence and metastasis. The method of fabrication utilized safe excipients and generated particles of 200 nm (PDI ≤ 0.2) with negative zeta potential (-30 mV) and a high yield of curcumin (95%), which can be converted by lyophilization to a dry powder. In vitro assays showed that CUR-NEM is safe in non-cancerous human cells (HEK-293T) and preferentially cytotoxic in gastric (AGS), colon (HT29-ATCC, HT29-US), breast (MDA-MB-231) and melanoma (B16F10) cells. In addition, in melanoma cells the nanoformulation increases intracellular curcumin accumulation and reactive oxygen species (ROS) formation, while preventing cell-migration and invasion. In vivo studies in C57BL/6 mice demonstrated that a single dose, applied topically to the wounded area after surgical excision of primary tumors formed upon subcutaneous injection of syngeneic B16F10 cells, was sufficient to completely prevent reincident tumor growth and spontaneous lung metastasis, while in untreated animals 70% reincidence and metastasis were observed. In vivo experiments also showed that the fluorescence signal due to curcumin was maintained at least 15 days after topical application of CUR-NEM, while when administered in DMSO the curcumin signal disappeared within 4 days. Importantly, the administration of a dose 22 times larger than that applied topically to animals after tumor surgery did not alter biochemical parameters. Due to the safety and efficacy of the formulation, we envisage it as ideal for topical application in cancer patients following surgery, to prevent tumor reincidence and metastasis. In addition, other routes of administration/protocols could also be proposed to treat/prevent malignant tumors in patients.

Topics: A549 Cells; Adenocarcinoma; Animals; Cell Line, Tumor; Cell Movement; Cell Survival; Curcumin; Drug Carriers; Emulsions; HEK293 Cells; Humans; Lung Neoplasms; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Nanoparticles; Neoplasm Metastasis; Neoplasms; Reactive Oxygen Species; Solvents

The fatality of cancer is mostly dependent on the possibility of occurrence of metastasis. Thus, if the development of metastasis can be prevented through novel therapeutic strategies targeted against this process, then the success of cancer treatment will drastically increase. In this study, therefore, we evaluated the antimetastatic potentials of an extract of Khaya senegalensis and curcumin on the metastatic liver cell line HepG2, and also assessed the anticancer property of the extract.. Cells were cultured and treated with graded concentrations of test substances for 24, 48, or 72 h with provisions made for negative controls. Treated cells were assessed as follows: nanotechnologically - atomic force microscopy (AFM) was used to determine cell stiffness; biochemically - cell cytotoxicity, glutathione level and adenosine triphosphate status, caspase activation and mitochondrial toxicity were considered; and microbiologically - a carrot disk assay was used to assess the anticancer property of the extract of K. senegalensis.. Curcumin and K. senegalensis increased the cell stiffness by 2.6- and 4.0-fold respectively, indicating their antimetastatic effects. Corresponding changes in redox (glutathione level) and energy (adenosine triphosphate) status of the cells were also demonstrated. Further mechanistic studies indicated that curcumin was not mitotoxic in HepG2 cells unlike the K. senegalensis extract. In addition, the extract potently inhibited the Agrobacterium tumefaciens-induced genetic transformation based on carrot disk assay.. Cell elasticity measurement data, using AFM, strongly suggested, for the first time, that both curcumin and the extract of K. senegalensis exhibited antimetastatic properties on HepG2 cells.

Topics: Adenosine Triphosphate; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Proliferation; Curcuma; Curcumin; Elasticity; Glutathione; Hep G2 Cells; Humans; Meliaceae; Microscopy, Atomic Force; Neoplasm Invasiveness; Neoplasm Metastasis; Oxidation-Reduction; Phytotherapy; Plant Extracts

Prostate cancer is one of the most common malignancies in men, and it urgently demands precise interventions that target the signaling pathways implicated in its initiation, progression, and metastasis. The Notch-1 signaling pathway is closely associated with the pathophysiology of prostate cancer. This study investigated the antitumor effects and mechanisms of curcumin, which is a well-known natural compound from curcuminoids, in prostate cancer cells. Viability, proliferation, and migration were analyzed in two prostate cancer cell lines, DU145 and PC3, after curcumin treatment. Whether the Notch-1 signaling pathway is involved in the antitumor effects of curcumin was examined. Curcumin inhibited the survival and proliferation of PC3 and DU145 cells in a dose- and time-dependent manner and inhibited DU145 migration. Curcumin did not affect the expression of Notch-1 or its active product NICD, but it did inhibit the expression of MT1-MMP and MMP2 proteins in DU145 cells. We found that curcumin inhibited the DNA-binding ability of NICD in DU145 cells. In conclusion, curcumin inhibited the survival and metastasis of prostate cancer cells via the Notch-1 signaling pathway.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Curcumin; Dose-Response Relationship, Drug; Gene Expression Profiling; Humans; Male; Matrix Metalloproteinase 14; Matrix Metalloproteinase 2; Neoplasm Metastasis; Prostatic Neoplasms; Receptor, Notch1; Signal Transduction; Time Factors

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

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

Androgen deprivation therapy (ADT) with the newly developed powerful anti-androgen enzalutamide (Enz, also known as MDV3100) has promising therapeutic effects to suppress castration resistant prostate cancer (CRPC) and extending patients' lives an extra 4.8 months. However, most Enz therapy eventually fails with the development of Enz resistance. The detailed mechanisms how CRPC develops Enz resistance remain unclear and may involve multiple mechanisms. Among them, the induction of the androgen receptor (AR) mutant AR-F876L in some CRPC patients may represent one driving force that confers Enz resistance. Here, we demonstrate that the AR degradation enhancer, ASC-J9(®), not only degrades wild-type AR, but also has the ability to target AR-F876L. The consequence of suppressing AR-F876L may then abrogate AR-F876L mediated CRPC cell proliferation and metastasis. Thus, developing ASC-J9(®) as a new therapeutic approach may represent a novel therapy to better suppress CRPC that has already developed Enz resistance.

Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Benzamides; Cell Line, Tumor; Cell Movement; Cell Proliferation; Curcumin; Drug Resistance, Neoplasm; Humans; Male; Mutation; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Proteolysis; Receptors, Androgen; Signal Transduction; Time Factors; Transcription, Genetic; Transfection

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

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

One of the approaches being explored to increase antitumor activity of chemotherapeutics is to inject drug-loaded microspheres locally to specific anatomic sites, providing for a slow, long term release of a chemotherapeutic while minimizing systemic exposure. However, the used clinically drug carriers available at present have limitations, such as their low stability, renal clearance and residual surfactant. Here, we report docetaxel (DOC) and curcumin (CUR) loaded nanofibrous microspheres (DOC + CUR/nanofibrous microspheres), self-assembled from biodegradable PLA-PEO-PPO-PEO-PLA polymers as an injectable drug carrier without adding surfactant during the emulsification process. The obtained nanofibrous microspheres are composed entirely of nanofibers and have an open hole on the shell without the assistance of a template. It was shown that these DOC + CUR/nanofibrous microspheres could release curcumin and docetaxel slowly in vitro. The slow, sustained release of curcumin and docetaxel in vivo may help maintain local concentrations of active drug. The mechanism by which DOC + CUR/nanofibrous microspheres inhibit colorectal peritoneal carcinomatosis might involve increased induction of apoptosis in tumor cells and inhibition of tumor angiogenesis. In vitro and in vivo evaluations demonstrated efficacious synergistic antitumor effects against CT26 of curcumin and docetaxel combined nanofibrous microspheres. In conclusion, the dual drug loaded nanofibrous microspheres were considered potentially useful for treating abdominal metastases of colorectal cancer.

Topics: Abdominal Neoplasms; Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Colonic Neoplasms; Curcumin; Docetaxel; Drug Carriers; Drug Screening Assays, Antitumor; Flow Cytometry; Hemolysis; Humans; Magnetic Resonance Spectroscopy; Mice; Mice, Inbred BALB C; Microspheres; Molecular Weight; Nanofibers; Nanoparticles; Neoplasm Metastasis; Poloxamer; Polymers; Spectroscopy, Fourier Transform Infrared; Taxoids; Thermogravimetry; X-Ray Diffraction

Although carboplatin is one of the standard chemotherapeutic agents for non-small cell lung cancer (NSCLC), it has limited therapeutic efficacy due to activation of a survival signaling pathway and the induction of multidrug resistance. Curcumin, a natural compound isolated from the plant Curcuma longa, is known to sensitize tumors to different chemotherapeutic agents. The aim of this study is to evaluate whether curcumin can chemosensitize lung cancer cells to carboplatin and to analyze the signaling pathway underlying this synergism. We investigated the synergistic effect of both agents on cell proliferation, apoptosis, invasion, migration, and expression of related signaling proteins using the human NSCLC cell line, A549. A549 cell was treated with different concentrations of curcumin and carboplatin alone and in combination. Combined treatment with curcumin and carboplatin inhibited tumor cell growth, migration, and invasion compared with either drug alone. Matrix metalloproteinase (MMP)-2 and MMP-9 were more efficiently downregulated by co-treatment than by each treatment alone. mRNA and protein expression of caspase-3 and caspase-9 and proapoptotic genes was increased in cells treated with a combination of curcumin and carboplatin, whereas expression of the antiapoptotic Bcl-2 gene was suppressed. Co-treatment of both agents substantially suppressed NF-κB activation and increased expression of p53. Phosphorylation of Akt, a protein upstream of NF-κB, was reduced, resulting in inhibition of the degradation of inhibitor of κB(IκBα), whereas the activity of extracellular signal-regulated kinase (ERK1/2) was enhanced. Our study demonstrated that the synergistic antitumor activity of curcumin combined with carboplatin is mediated by multiple mechanisms involving suppression of NF-κB via inhibition of the Akt/IKKα pathway and enhanced ERK1/2 activity. Based on this mechanism, curcumin has potential as a chemosensitizer for carboplatin in the treatment of patients with NSCLC.

Topics: Antineoplastic Agents; Apoptosis; Carboplatin; Carcinoma, Non-Small-Cell Lung; Caspase 3; Caspase 9; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Curcumin; Drug Screening Assays, Antitumor; Drug Synergism; Extracellular Signal-Regulated MAP Kinases; Humans; Lung Neoplasms; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Neoplasm Invasiveness; Neoplasm Metastasis; Phosphorylation; Wound Healing

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

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

The study was aimed to evaluate the effect of orally administered chitosan-coated nanoparticles containing curcumin on metastatic melanoma. Chitosan-coated nanoparticles containing curcumin were prepared, and their antimetastatic activity was investigated both in vitro and in vivo. Curcumin decreased cell viability and induced apoptosis of B16F10 melanoma cells. We observed that curcumin significantly decreased the expression of metalloproteinases, which are known to be associated with migration and proliferation of cancer cells. Importantly, treatment with chitosan-coated nanoparticles containing curcumin decreased pulmonary tumor formation in a murine model of experimental metastasis. Histological analyses confirmed the macroscopic results in which lungs of mice treated with curcumin-loaded chitosan-coated polycaprolactone nanoparticles had only a few small nodules and most of them were free of melanoma. Our findings indicate that nanoparticles coated with the mucoadhesive polymer chitosan containing curcumin may be a promising approach and/or intervention for the treatment of malignant melanoma.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Line, Tumor; Cell Movement; Chitosan; Curcumin; Female; Intestinal Absorption; Matrix Metalloproteinase 2; Melanoma; Melanoma, Cutaneous Malignant; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Nanoparticles; Neoplasm Metastasis; Polyesters; Skin Neoplasms

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

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

Colon cancer is the third most commonly diagnosed cancer and the second leading cause of cancer mortality worldwide. Chalcone and its derivatives are reported to exhibit anti-cancer effects in several cancer cell lines, including colon cancer cells. In addition, chalcones have advantages such as poor interaction with DNA and low risk of mutagenesity. In our previous study, a group of chalcone derivatives were synthesized and exhibited strong anti-inflammatory activities. In this study, we evaluated the anti-cancer effects of the chalcone derivative, L2H17, in colon cancer cells.. The cytotoxicities of L2H17 on various colon cancer cell lines were investigated by MTT and clonogenic assay. Cell cycle and apoptosis analysis were performed to evaluate the molecular mechanism of L2H17-mediated inhibition of tumor growth. Also, scratch wound and matrigel invasion experiments were performed to estimate the cell migration and invasion after L2H17 treatment. Finally, we observed the anti-colon cancer effects of L2H17 in vivo.. Our data show that compound L2H17 exhibited selective cytotoxic effect on colon cancer cells, via inducing G0/G1 cell cycle arrest and apoptosis in CT26.WT cells. Furthermore, L2H17 treatment decreased cell migration and invasion of CT26.WT cells. In addition, L2H17 possessed marked anti-tumor activity in vivo. The molecular mechanism of L2H17-mediated inhibition of tumor promotion and progression were function through inactivated NF-κB and Akt signaling pathways.. All these findings show that L2H17 might be a potential growth inhibitory chalcones derivative for colon cancer cells.

Topics: Animals; Anticarcinogenic Agents; Apoptosis; Cell Movement; Chalcone; Chalcones; Chemoprevention; Colonic Neoplasms; Curcumin; G1 Phase Cell Cycle Checkpoints; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humans; Mice; Neoplasm Metastasis; NF-kappa B; Proto-Oncogene Proteins c-akt; Signal Transduction; Xenograft Model Antitumor Assays

Recent evidence indicating that phthalates promote cancer development, including cell proliferation, migration, and invasion, has raised public health concerns. Here, we show that bis(2-ethylhexyl) phthalate promotes the migration, invasion, and epithelial-mesenchymal transition of hepatocellular carcinoma cells. In addition, bis(2-ethylhexyl) phthalate increased the proportion of cancer stem cell (CSC)-like cells and stemness maintenance in vitro as well as tumor growth and metastasis in vivo. The various activities of curcumin, including anticancer, anti-inflammation, antioxidation, and immunomodulation, have been investigated extensively. Curcumin suppressed phthalate-induced cell migration, invasion, and epithelial-mesenchymal transition, decreased the proportion of CSC-like cells in hepatocellular carcinoma cell lines in vitro, and inhibited tumor growth and metastasis in vivo. We also reveal that curcumin suppressed phthalate-induced migration, invasion, and CSC-like cell maintenance through inhibition of the aryl hydrocarbon receptor/ERK/SK1/S1P3 signaling pathway. Our results suggest that curcumin may be a potential antidote for phthalate-induced cancer progression.

Topics: Animals; Carcinoma, Hepatocellular; Cell Movement; Curcumin; Extracellular Signal-Regulated MAP Kinases; Humans; Liver Neoplasms; Male; Mice, Inbred BALB C; Neoplasm Metastasis; Neoplastic Stem Cells; Phthalic Acids; Receptors, Aryl Hydrocarbon; Signal Transduction; Small-Conductance Calcium-Activated Potassium Channels

Adipose tissue is now considered as an endocrine organ involved in metabolic and inflammatory reactions. Adiponectin, a 244-amino acid peptide hormone, is associated with insulin resistance and carcinogenesis. Curcumin (diferuloylmethane) is the principal curcuminoid of the popular Indian spice, turmeric. Curcumin possesses antitumor effects, including the inhibition of neovascularization and regulation of cell cycle and apoptosis. However, the effects of adiponectin and curcumin on non-small cell lung cancer (NSCLC) remain unclear. In this study, we evaluated the expression of adiponectin in paired tumors and normal lung tissues from 77 patients with NSCLC using real-time polymerase chain reaction, western blotting, and immunohistochemistry. Kaplan-Meier survival analysis showed that patients with low adiponectin expression ratio (<1) had significantly longer survival time than those with high expression ratio (>1) (p = 0.015). Curcumin inhibited the migratory and invasive ability of A549 cells via the inhibition of adiponectin expression by blocking the adiponectin receptor 1. Curcumin treatment also inhibited the in vivo tumor growth of A549 cells and adiponectin expression. These results suggest that adiponectin can be a prognostic indicator of NSCLC. The effect of curcumin in decreasing the migratory and invasive ability of A549 cells by inhibiting adiponectin expression is probably mediated through NF-κB/MMP pathways. Curcumin could be an important potential adjuvant therapeutic agent for lung cancer in the future.

Topics: Adiponectin; Adult; Aged; Animals; Anti-Inflammatory Agents, Non-Steroidal; Blotting, Western; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Movement; Curcumin; Female; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Lung Neoplasms; Male; Matrix Metalloproteinases; Mice, SCID; Middle Aged; Neoplasm Metastasis; NF-kappa B; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Signal Transduction; Xenograft Model Antitumor Assays

Recent population studies provide clues that the use of curcumin may be associated with reduced incidence and improved prognosis of certain cancers. In the present study, we demonstrated that curcumin acted as a growth inhibitor for lung cancer cells. Our results found that curcumin inhibited cell proliferation, which was associated with upregulation of the cyclin-dependent kinase inhibitors, p27 and p21, and downregulation of cyclin D1. In addition, we showed that curcumin induced the expression of forkhead box protein O1 (FOXO1) through activation of extracellular signal-regulated kinase 1/2 signaling. These findings provide evidence for a mechanism that may contribute to the antineoplastic effects of curcumin and justify further work to explore potential roles for activators of FOXO1 in the prevention and treatment of lung cancer.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Curcumin; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Disease Progression; Dose-Response Relationship, Drug; Forkhead Box Protein O1; Forkhead Transcription Factors; Humans; Lung Neoplasms; MAP Kinase Signaling System; Neoplasm Metastasis

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

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

This study investigated the influence of curcumin on HOX transcript antisense RNA (HOTAIR)- mediated migration of cultured renal cell carcinoma (RCC) cells.. Five RCC cell lines (769-P, 769-P-vector, 769-P-HOTAIR, 786-0, and Kert-3 ) were maintained in vitro. The expression of HOTAIR mRNA was determined by quantitative real-time PCR and cell migration was measured by transwell migration assay. The effects of different concentrations of curcumin (0 to 80 μmol/L) on cell proliferation was determined by the CCK-8 assay and influence of non-toxic levels (0 to 10 μM) on the migration of RCC cells was also determined.. Comparison of the 5 cell lines indicated a correlation between HOTAIR mRNA expression and cell migration. In particular, the migration of 769-P-HOTAIR cells was significantly higher than that of 769-P-vector cells. Curcumin at 2.5-10 μM had no evident toxicity against RCC cells, but inhibited cell migration in a concentration-dependent manner.. HOTAIR expression is correlated with the migration of RCC cells, and HOTAIR may be involved in the curcumin-induced inhibition of RCC metastasis.

Topics: Carcinoma, Renal Cell; Cell Line, Tumor; Cell Movement; Cell Proliferation; Curcumin; Gene Expression Regulation, Neoplastic; Humans; Kidney Neoplasms; Neoplasm Invasiveness; Neoplasm Metastasis; RNA, Long Noncoding

Furanodiene (FUR) is a natural terpenoid isolated from Rhizoma curcumae, a well-known Chinese medicinal herb that presents anti-proliferative activities in several cancer cell lines. Herein, we systematically investigated the effects of FUR on the significant processes of tumor progression with the relatively low concentrations in 95-D lung cancer cells. FUR concentration-dependently inhibited cell proliferation and blocked the cell cycle progressions in G1 phase by down-regulating the protein levels of cyclin D1 and CDK6, and up-regulating those of p21 and p27 in 95-D cells. FUR also affected the signaling molecules that regulate apoptosis in 95-D cells revealed by the down-regulation of the protein levels of full PARP, pro-caspase-7, survivin, and Bcl-2, and the up-regulation of cleaved PARP. Further studies showed that FUR enhanced the expression of light chain 3-II (LC3-II) in the protein level, indicating that autophagy is involved in this process. Besides, the adhesion ability of 95-D cells to matrigel and fibronectin was slightly inhibited after FUR treatment for 1 h in our experimental condition. FUR also slightly suppressed cell migration and invasion in 95-D cells according to the data from wound healing and Transwell assays, respectively. Taken together, FUR activated the signal molecules regulating G1 cell cycle arrest, apoptosis and autophagy, while slightly affecting the key steps of cell metastasis in 95-D lung cancer cells in the relatively low concentrations.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Autophagy; Caspase 7; Curcuma; Dose-Response Relationship, Drug; Furans; G1 Phase Cell Cycle Checkpoints; Heterocyclic Compounds, 2-Ring; Humans; Inhibitor of Apoptosis Proteins; Lung Neoplasms; Neoplasm Metastasis; Poly(ADP-ribose) Polymerases; Proto-Oncogene Proteins c-bcl-2; Rhizome; Survivin; Tumor Cells, Cultured

Coptidis Rhizoma and Aconiti Kusnezoffii Radix represent hot Chinese medicine and cold Chinese medicine respectively. The purpose of this study is to observe the differentiation effect of Coptidis Rhizoma and Aconiti Kusnezoffii Radix on lewis lung cancer and compare effect of hot Chinese medicine and cold Chinese medicine on tumor progression. In this study, the rat serum containing Coptidis Rhizoma or Aconiti Kusnezoffii Radix was prepared to treat lewis lung cancer cells in vitro, and effects of the serum containing Coptidis Rhizoma or Aconiti Kusnezoffii Radix on cell differentiation, proliferation, adhesion, succinic dehydrogenase (SDH) activity and gap-junction intercellular communication (GJIC) were investigated. In vivo, the subcutaneous implant model and pulmonary metastasis model of lewis lung cancer were established. Tumor bearing mice were taken water decoction of coptis chinensis or aconite by intragastric administration bid for four weeks, and the influences of coptis chinensis and aconite on tumor progression were evaluated by body temperature, blood oxygen saturation, red cell ATPase, blood rheology, intratumor hypoxia, capillary permeability and GJIC. The results showed that the serum containing aconite could induce cell differentiation, inhibit cell proliferation and migration, promote SDH activity and GJIC in lewis lung cancer cells. The serum containing Coptidis Rhizoma increased cell adhesion and decreased SDH activity and GJIC without cell differentiation although it also suppressed cell proliferation. Aconiti Kusnezoffii Radix water decoction could keep body temperature, blood oxygen saturation, red cell ATPase and blood rheology, and improve intratumor hypoxia, capillary permeability and GJIC in tumor bearing mice, which led to slower tumor growth and less metastasis. Coptidis Rhizoma water decoction decreased body temperature, blood oxygen saturation, red cell ATPase, blood rheology and GJIC, and promoted intratumor hypoxia and capillary permeability, which resulted to more tumor metastasis although it also prevented tumor growth. These results suggested that the hot Chinese medicine could induce tumor cell differentiation and prevent tumor poison invagination, which is better for tumor treatment than cold Chinese medicine.

Topics: Aconitum; Animals; Antineoplastic Agents; Carcinoma, Lewis Lung; Cell Differentiation; Cell Line, Tumor; Curcuma; Drugs, Chinese Herbal; Mice; Neoplasm Metastasis; Rats; Xenograft Model Antitumor Assays

Curcumin, the active constituent of dietary spice turmeric, possesses a strong potential for cancer prevention and treatment. However, there is no study to address the effects of curcumin on invasion and metastasis of thyroid cancers. Thyroid cancer is the most common malignancy of endocrine organs, and its incidence rates have steadily increased over recent decades. Although most indolent tumours can be effectively managed, metastatic tumours at distant secondary sites behave aggressively and currently there is no effective form of treatment. Here, for the first time it has been reported that curcumin inhibit multiple metastasis steps of K1 papillary thyroid cancer cells. Curcumin dose-dependently suppressed viability of K1 cells as well as its cell attachment, spreading, migration and invasion abilities. Moreover, curcumin could also down-regulate the expression and activity of matrix metalloproteinase-9 (MMP-9). The findings showed that curcumin might be an effective tumouristatic agent for the treatment of aggressive papillary thyroid carcinomas.

Topics: Carcinoma; Carcinoma, Papillary; Cell Line, Tumor; Cell Movement; Curcumin; Down-Regulation; Gene Expression Regulation, Neoplastic; Humans; Matrix Metalloproteinase 9; Neoplasm Invasiveness; Neoplasm Metastasis; Thyroid Cancer, Papillary; Thyroid Neoplasms

Despite androgen deprivation therapy (ADT) suppression of prostate cancer (PCa) growth, its overall effects on PCa metastasis remain unclear. Using human (C4-2B/THP1) and mouse (TRAMP-C1/RAW264.7) PCa cells-macrophages co-culture systems, we found currently used anti-androgens, MDV3100 (enzalutamide) or Casodex (bicalutamide), promoted macrophage migration to PCa cells that consequently led to enhanced PCa cell invasion. In contrast, the AR degradation enhancer, ASC-J9, suppressed both macrophage migration and subsequent PCa cell invasion. Mechanism dissection showed that Casodex/MDV3100 reduced the AR-mediated PIAS3 expression and enhanced the pSTAT3-CCL2 pathway. Addition of CCR2 antagonist reversed the Casodex/MDV3100-induced macrophage migration and PCa cell invasion. In contrast, ASC-J9 could regulate pSTAT3-CCL2 signaling using two pathways: an AR-dependent pathway via inhibiting PIAS3 expression and an AR-independent pathway via direct inhibition of the STAT3 phosphorylation/activation. These findings were confirmed in the in vivo mouse model with orthotopically injected TRAMP-C1 cells. Together, these results may raise the potential concern about the currently used ADT with anti-androgens that promotes PCa metastasis and may provide some new and better therapeutic strategies using ASC-J9 alone or a combinational therapy that simultaneously targets androgens/AR signaling and PIAS3-pSTAT3-CCL2 signaling to better battle PCa growth and metastasis at castration-resistant stage.

Topics: Androgen Antagonists; Androgen Receptor Antagonists; Anilides; Animals; Antineoplastic Agents; Benzamides; Cell Movement; Chemokine CCL3; Coculture Techniques; Curcumin; Humans; Macrophages; Male; Mice; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Signal Transduction; STAT3 Transcription Factor; Tosyl Compounds

Infection with Helicobacter pylori is important in the development and progression of gastric cancer. However, the mechanisms that regulate this activation in gastric tumors remain elusive. CACUL1 has been cloned and identified as a novel gene that is expressed in many types of cancer and is involved in cell cycle regulation and tumor growth. The current study aimed to examine the expression of CACUL1 in gastric cancer samples and analyze its correlation with H. pylori infection. We found that CACUL1 was highly expressed in gastric cancer tissues and negatively correlated with gastric cancer differentiation and TNM stage. In addition, CACUL1 expression was high in H. pylori-infected tissues compared with H. pylori non-infected tissue. We found that H. pylori could up-regulate CACUL1 expression through activating protein 1. The up-regulation of CACUL1 expression could promote matrix metalloproteinase 9 and Slug expression to increase invasion and metastasis of tumor cells. These results suggested that H. pylori-triggered CACUL1 production occurred in an activating protein 1-dependent manner and regulated matrix metalloproteinase 9 and Slug expression to affect the invasion and metastasis of tumor cells. Therefore, CACUL1 is a potential therapeutic target for the treatment of aggressive gastric cancer.

Topics: Adult; Aged; Aged, 80 and over; Animals; Anthracenes; Cell Line, Tumor; Cullin Proteins; Curcumin; Female; Gastric Mucosa; Gene Expression Regulation, Neoplastic; Helicobacter pylori; Humans; Male; Matrix Metalloproteinase 9; Mice; Middle Aged; Neoplasm Invasiveness; Neoplasm Metastasis; Phosphorylation; Promoter Regions, Genetic; Proto-Oncogene Proteins c-fos; Stomach; Stomach Neoplasms; Transcription Factor AP-1; Transcriptional Activation; Up-Regulation; Young Adult

Success of cancer vaccination is strongly hampered by immune suppression in the tumor microenvironment (TME). Interleukin (IL)-6 is particularly and highly produced by triple-negative breast cancer (TNBC) cells, and has been considered as an important contributor to immune suppression in the TME. Therefore, we hypothesized that IL-6 reduction may improve efficacy of vaccination against TNBC cancer through improved T-cell responses. To prove this hypothesis, we investigated the effect of curcumin, an inhibitor of IL-6 production, on vaccination of a highly attenuated Listeria monocytogenes (Listeria(at)), encoding tumor-associated antigens (TAA) Mage-b in a TNBC model 4T1. Two therapeutic vaccination strategies with Listeria(at)-Mage-b and curcumin were tested. The first immunization strategy involved all Listeria(at)-Mage-b vaccinations and curcumin after tumor development. As curcumin has been consumed all over the world, the second immunization strategy involved curcumin before and all therapeutic vaccinations with Listeria(at)-Mage-b after tumor development. Here, we demonstrate that curcumin significantly improves therapeutic efficacy of Listeria(at)-Mage-b with both immunization strategies particularly against metastases in a TNBC model (4T1). The combination therapy was slightly but significantly more effective against the metastases when curcumin was administered before compared to after tumor development. With curcumin before tumor development in the combination therapy, the production of IL-6 was significantly decreased and IL-12 increased by myeloid-derived suppressor cells (MDSC), in correlation with improved CD4 and CD8 T-cell responses in blood. Our study suggests that curcumin improves the efficacy of Listeria(at)-Mage-b vaccine against metastases in TNBC model 4T1 through reversal of tumor-induced immune suppression.

Topics: Animals; Antineoplastic Agents; Apoptosis; Bacterial Vaccines; Cancer Vaccines; Cell Line, Tumor; Cell Proliferation; Curcumin; Disease Models, Animal; Female; Immunization; Interleukin-12; Interleukin-6; Listeria monocytogenes; Mammary Neoplasms, Experimental; Mice; Myeloid Cells; Neoplasm Metastasis; T-Lymphocyte Subsets; Triple Negative Breast Neoplasms

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

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

Lung carcinogenesis is a complex process in an unregulated inflammatory environment. Curcumin has been extensively investigated as a multi-target anti-tumor and anti-inflammation compound. In this paper, we demonstrate a novel inflammation-related mechanism for curcumin-induced inhibition of lung tumor growth. We found that neutrophil elastase, an important regulator of inflammatory processes, directly triggered tumor cell proliferation in human lung adenocarcinoma A549 cells, and curcumin could completely suppress the excess tumor proliferation induced by neutrophil elastase. α1-antitrypsin is synthesized by tumor cells and is the natural inhibitor of neutrophil elastase. We found that curcumin counteracted the decrease of α1-antitrypsin induced by neutrophil elastase by inducing the promoter activity of α1-antitrypsin and promoting its expression in A549 cells. The inhibition of neutrophil elastase-induced proliferation by curcumin was dependent on the PI3K/Akt pathway. Knockdown of α1-antitrypsin by siRNA further enhanced the tumor cell proliferation induced by neutrophil elastase and significantly blocked the anti-proliferation effect of curcumin against neutrophil elastase. Curcumin remarkably inhibited the primary tumor growth of Lewis lung carcinoma (LLC) in C57BL/6 mice. We further showed that curcumin upregulated the level of α1-antitrypsin in primary tumor tissue by promoting its local expression, and the protein level of neutrophil elastase in tumor tissue was obviously decreased in mice treated with curcumin. Overall, our results suggest that neutrophil elastase and α1-antitrypsin play important roles in modulating lung tumor proliferation in inflammatory microenvironment and curcumin inhibits neutrophil elastase-induced tumor proliferation via upregulating α1-antitrypsin expression in vitro and in vivo.

Topics: alpha 1-Antitrypsin; Animals; Carcinoma, Lewis Lung; Cell Line, Tumor; Cell Proliferation; Curcumin; Female; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Leukocyte Elastase; Lung Neoplasms; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; RNA, Small Interfering; Signal Transduction; Up-Regulation

Cell migration is an early-stage and critical step for cancer metastasis. The most common approach to monitor this process is wound-healing assay. However, this traditional method has some unavoidable limitations. We observed that simply scratching the monolayer of cultured cells might cause local cell damage around the injury line. The cells along the scratched border seemed to be irritated and exhibited abnormal distribution of cytoskeleton reassembly with protruding "cell islands" and "pseudopodia" during wound healing, which might potentially affect the assessment of cell migration behavior. Herein, we applied a microfluidic device that mechanically constrained cells seeded in a designed pattern inside microchannels, and monitored cell movement in a way of mimicking the natural microenvironment of cancerous tissues. We illustrated the capacity of this simple method to probe cellular migration behaviors and to screen some biological active agents that reflected in their influence on cellular motility.

Topics: Analysis of Variance; Apigenin; Cell Line, Tumor; Cell Movement; Cells, Cultured; Curcumin; Cytological Techniques; Humans; Microfluidic Analytical Techniques; Neoplasm Metastasis

Breast cancers with an overexpression of Her-2 or Skp2 overlap with those affected by reduced p27 expression. In breast cancer, the loss of p27 is associated with a poor prognosis. Curcumin, the main constituent of turmeric, has been found to stabilize p27 levels in breast cancer, but whether this effect is mediated through changes in Skp2 or Her2 expression remains unclear. This study investigates whether curcumin inhibits Skp2-mediated p27 ubiquitination in Her2/Skp2-overexpressing cancer cell lines (MDA-MB-231/Her2 cells). The results show that curcumin represses cell proliferation, induces G1 arrest at a lower dosage (30μM), triggers apoptosis at a higher dosage (50μM) and blocks cell migration in MDA-MB-231/Her2 cells. A low dose of curcumin increases p27 and decreases Skp2, Her2, Cyclin E, CDK kinases in a time- and dose-dependent manner, suggesting that p27, Skp2 and Her2 may be involved in the growth inhibition in MDA-MB-231/Her2 cells induced by curcumin. However, higher doses of curcumin produce a dose-dependent apoptotic death in MDA-MB-231/Her2 cells, which is related to cleaved forms of PARP and caspase 3. The findings indicate that curcumin is of potential value for the chemoprevention of breast cancer, especially in breast cancer with Skp2/Her2 overexpression.

Topics: Antineoplastic Agents; Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Movement; Cell Proliferation; Curcumin; Cyclin-Dependent Kinase Inhibitor p27; Down-Regulation; Extracellular Signal-Regulated MAP Kinases; Gene Expression Regulation, Neoplastic; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Neoplasm Metastasis; Phosphorylation; Proto-Oncogene Proteins c-akt; Receptor, ErbB-2; S-Phase Kinase-Associated Proteins; Transcription, Genetic; Ubiquitination

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

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

Histone deacetylase inhibitors (HDACi) are actively explored as new-generation epigenetic drugs but have low efficacy in cancer monotherapy. To reveal new mechanism for combination therapy, we show that HDACi induce cell death but simultaneously activate tumor-progressive genes to ruin therapeutic efficacy. Combined treatments to target tumorigenesis and HDACi-activated metastasis with low toxic modalities could develop new strategies for long-term cancer therapy.. Because metastasis is the major cause of cancer mortality, we measured cell migration activity and profiled metastasis-related gene expressions in HDACi-treated cancer cells. We developed low toxic combination modalities targeting tumorigenesis and HDACi-activated metastasis for preclinical therapies in mice.. We showed that cell migration activity was dramatically and dose dependently enhanced by various classes of HDACi treatments in 13 of 30 examined human breast, gastric, liver, and lung cancer cell lines. Tumor metastasis was also enhanced in HDACi-treated mice. HDACi treatments activated multiple PKCs and downstream substrates along with upregulated proapoptotic p21. For targeting tumorigenesis and metastasis with immediate clinical impact, we showed that new modalities of HDACi combined drugs with PKC inhibitory agent, curcumin or tamoxifen, not only suppressed HDACi-activated tumor progressive proteins and cell migration in vitro but also inhibited tumor growth and metastasis in vivo.. Treatments of different structural classes of HDACi simultaneously induced cell death and promoted cell migration and metastasis in multiple cancer cell types. Suppression of HDACi-induced PKCs leads to development of low toxic and long-term therapeutic strategies to potentially treat cancer as a chronic disease.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Movement; Cell Survival; Cell Transformation, Neoplastic; Combined Modality Therapy; Curcumin; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Mice; Neoplasm Metastasis; Neoplasms; Protein Kinase C; Tamoxifen

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

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

In America and Western Europe, prostate cancer is the second leading cause of death in men. Emerging evidence suggests that chronic inflammation is a major risk factor for the development and metastatic progression of prostate cancer. We previously reported that the chemopreventive polyphenol curcumin inhibits the expression of the proinflammatory cytokines CXCL1 and -2 leading to diminished formation of breast cancer metastases. In this study, we analyze the effects of curcumin on prostate carcinoma growth, apoptosis and metastasis. We show that curcumin inhibits translocation of NFκB to the nucleus through the inhibition of the IκB-kinase (IKKβ, leading to stabilization of the inhibitor of NFκB, IκBα, in PC-3 prostate carcinoma cells. Inhibition of NFκB activity reduces expression of CXCL1 and -2 and abolishes the autocrine/paracrine loop that links the two chemokines to NFκB. The combination of curcumin with the synthetic IKKβ inhibitor, SC-541, shows no additive or synergistic effects indicating that the two compounds share the target. Treatment of the cells with curcumin and siRNA-based knockdown of CXCL1 and -2 induce apoptosis, inhibit proliferation and downregulate several important metastasis-promoting factors like COX2, SPARC and EFEMP. In an orthotopic mouse model of hematogenous metastasis, treatment with curcumin inhibits statistically significantly formation of lung metastases. In conclusion, chronic inflammation can induce a metastasis prone phenotype in prostate cancer cells by maintaining a positive proinflammatory and prometastatic feedback loop between NFκB and CXCL1/-2. Curcumin disrupts this feedback loop by the inhibition of NFκB signaling leading to reduced metastasis formation in vivo.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Chemokine CXCL1; Chemokine CXCL2; Curcumin; Humans; Male; Mice; Neoplasm Metastasis; NF-kappa B; Prostatic Neoplasms; Signal Transduction; 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

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

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

Curcumin or diferuloylmethane is a yellow polyphenol extracted from the rhizome of turmeric (Curcuma longa). A large volume (several hundreds) of published reports has established the anticancer and chemopreventative properties of curcumin in preclinical models of every known major cancer type. Nevertheless, the clinical translation of curcumin has been significantly hampered due to its poor systemic bioavailability, which mandates that patients consume up to 8 to 10 g of the free drug orally each day to achieve detectable levels in circulation. We have engineered a polymeric nanoparticle encapsulated curcumin formulation (NanoCurc) that shows remarkably higher systemic bioavailability in plasma and tissues compared with free curcumin upon parenteral administration. In xenograft models of human pancreatic cancer established in athymic mice, administration of parenteral NanoCurc significantly inhibits primary tumor growth in both subcutaneous and orthotopic settings. The combination of parenteral NanoCurc with gemcitabine results in enhanced tumor growth inhibition versus either single agent, suggesting an additive therapeutic influence in vivo. Furthermore, this combination completely abrogates systemic metastases in orthotopic pancreatic cancer xenograft models. Tumor growth inhibition is accompanied by significant reduction in activation of nuclear factor-kappaB, as well as significant reduction in expression of matrix metalloproteinase-9 and cyclin D1, in xenografts treated with NanoCurc and gemcitabine. NanoCurc is a promising new formulation that is able to overcome a major impediment for the clinical translation of curcumin to cancer patients by improving systemic bioavailability, and by extension, therapeutic efficacy.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Biological Availability; Cell Line, Tumor; Cell Proliferation; Curcumin; Cyclin D1; Deoxycytidine; Disease Models, Animal; Down-Regulation; Drug Synergism; Gemcitabine; Humans; Matrix Metalloproteinase 9; Mice; Nanoparticles; Neoplasm Metastasis; NF-kappa B; Pancreatic Neoplasms; Polymers; Subcutaneous Tissue; Xenograft Model Antitumor Assays

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

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

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

To study the effect of curcumin on invasion and migration of the tongue squamous cell line Tca8113.. Tca8113 cells were treated with curcumin (0 - 100 micromol/L) for 24 h and the conditional medium was collected. The gelatinases - matrix metalloproteinase -2 and -9 (MMP-2, -9) in the conditional medium were detected by gelatin zymography. The cell invasion and migration model in vitro was conducted using transwell chamber with or without matrigel. Using this model, the effects of 50 micromol/L curcumin on invasion and migration of Tca8113 were detected.. Curcumin reduced the activities of MMP-2 and MMP-9 on a dose-dependent manner. Curcumin can suppress cell invasion and migration significantly (P <0.01).. Curcumin can suppress Tca8113 invasion and migration by reducing the activities of MMP-2 and MMP-9.

Topics: Carcinoma, Squamous Cell; Cell Line, Tumor; Curcumin; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Neoplasm Metastasis; Tongue Neoplasms

Curcumin (diferuloylmethane) is an active component of the spice turmeric and has a diversity of antitumor activities. In this study, we found that curcumin can inhibit cancer cell invasion and metastasis through activation of the tumor suppressor DnaJ-like heat shock protein 40 (HLJ1). Human lung adenocarcinoma cells (CL1-5) treated with curcumin (1-20 mumol/L) showed a concentration-dependent reduction in cell migration, invasion, and metastatic ability, and this was associated with increased HLJ1 expression. Knockdown of HLJ1 expression by siRNA was able to reverse the curcumin-induced anti-invasive and antimetastasis effects in vitro and in vivo. The HLJ1 promoter and enhancer in a luciferase reporter assay revealed that curcumin transcriptionally up-regulates HLJ1 expression through an activator protein (AP-1) site within the HLJ1 enhancer. JunD, one of the AP-1 components, was significantly up-regulated by curcumin (1-20 mumol/L) in a concentration- and time-dependent manner. Knockdown of JunD expression could partially reduce the curcumin-induced HLJ1 activation and diminish the anti-invasive effect of curcumin, indicating that JunD would seem to be involved in curcumin-induced HLJ1 expression. Curcumin was able to induce c-Jun NH(2)-kinase (JNK) phosphorylation, whereas the JNK inhibitor (SP-600125) could attenuate curcumin-induced JunD and HLJ1 expression. Activation of HLJ1 by curcumin further leads to up-regulation of E-cadherin and a suppression of cancer cell invasion. Our results show that curcumin induces HLJ1, through activation of the JNK/JunD pathway, and inhibits lung cancer cell invasion and metastasis by modulating E-cadherin expression. This is a novel mechanism and supports the application of curcumin in anti-cancer metastasis therapy.

Topics: Adenocarcinoma; Animals; Cadherins; Cell Line, Tumor; Cell Movement; Curcumin; HSP40 Heat-Shock Proteins; Humans; Lung Neoplasms; MAP Kinase Kinase 4; Mice; Mice, SCID; Neoplasm Invasiveness; Neoplasm Metastasis; Proto-Oncogene Proteins c-jun; Random Allocation; Signal Transduction; Transcription Factor AP-1; Transfection; Up-Regulation

We have recently shown that curcumin (a diferuloylmethane, the yellow pigment in turmeric) enhances apoptosis-inducing potential of TRAIL in prostate cancer PC-3 cells, and sensitizes TRAIL-resistant LNCaP cells in vitro through multiple mechanisms. The objectives of this study were to investigate the molecular mechanisms by which curcumin sensitized TRAIL-resistant LNCaP xenografts in vivo.. Prostate cancer TRAIL-resistant LNCaP cells were implanted in Balb c nude mice to examine the effects of curcumin and/or TRAIL on tumor growth and genes related to apoptosis, metastasis and angiogenesis.. Curcumin inhibited growth of LNCaP xenografts in nude mice by inducing apoptosis (TUNEL staining) and inhibiting proliferation (PCNA and Ki67 staining), and sensitized these tumors to undergo apoptosis by TRAIL. In xenogrfated tumors, curcumin upregulated the expression of TRAIL-R1/DR4, TRAIL-R2/DR5, Bax, Bak, p21/WAF1, and p27/KIP1, and inhibited the activation of NFkappaB and its gene products such as cyclin D1, VEGF, uPA, MMP-2, MMP-9, Bcl-2 and Bcl-XL. The regulation of death receptors and members of Bcl-2 family, and inactivation of NFkappaB may sensitize TRAIL-resistant LNCaP xenografts. Curcumin also inhibited number of blood vessels in tumors, and circulating endothelial growth factor receptor 2-positive endothelial cells in mice.. The ability of curcumin to inhibit tumor growth, metastasis and angiogenesis, and enhance the therapeutic potential of TRAIL suggests that curcumin alone or in combination with TRAIL can be used for prostate cancer prevention and/or therapy.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Curcumin; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p21; Cyclooxygenase 2; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Humans; Interleukin-2; Mice; Mice, Nude; Neoplasm Metastasis; Neovascularization, Pathologic; NF-kappa B; Proto-Oncogene Proteins c-bcl-2; Receptors, Death Domain; TNF-Related Apoptosis-Inducing Ligand; Xenograft Model Antitumor Assays

The natural pigments curcumin and berberine have been shown to exhibit a variety of pharmacologic effects including anti-inflammatory, anti-cancer, and anti-metastatic properties. Here, we investigated the anti-lymphangiogenic effect with an in vitro tube-forming model using conditionally immortalized lymphatic endothelial TR-LE cells, a newly established cell line originating from the thoracic duct of a transgenic rat expressing the temperature-sensitive SV40 large T-antigen. Curcumin, but not berberine, exhibited a dose-dependent inhibition of the formation of capillary-like tubes by TR-LE cells without affecting cell viability and adhesion to Matrigel. To address the molecular mechanisms involved, we performed experiments with specific inhibitors against putative targets of curcumin, including IkappaB kinase (IKK), epidermal growth factor receptor (EGFR), phosphatidylinositol-3 kinase (PI3K)/Akt, and matrix metalloproteinases (MMPs). While the IKK-2 inhibitor VI and EGFR tyrosine kinase inhibitors gefitinib and PD153035 had no effect, both the PI3K inhibitor LY294002 and the MMP inhibitor GM6001 shortened the tubes by approximately 50%. Western blot analysis and gelatin zymography revealed that curcumin, but not berberine, has an inhibitory effect on the phosphorylation of Akt and enzymatic activity of MMP-2 in TR-LE cells. These results suggest that curcumin exerts its inhibitory effect on lymphangiogenesis partly through Akt and MMP-2.

Topics: Animals; Berberine; Capillaries; Cell Adhesion; Cell Line, Tumor; Cell Survival; Curcumin; Dose-Response Relationship, Drug; Endothelial Cells; I-kappa B Kinase; Matrix Metalloproteinase 2; Neoplasm Metastasis; Proto-Oncogene Proteins c-akt; Rats

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

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

Curcumin (diferuloylmethane), an anti-inflammatory agent used in traditional medicine, has been shown to suppress cellular transformation, proliferation, invasion, angiogenesis, and metastasis through a mechanism not fully understood. Because several genes that mediate these processes are regulated by nuclear factor-kappaB (NF-kappaB), we have postulated that curcumin mediates its activity by modulating NF-kappaB activation. Indeed, our laboratory has shown previously that curcumin can suppress NF-kappaB activation induced by a variety of agents (J Biol Chem 270:24995-50000, 1995). In the present study, we investigated the mechanism by which curcumin manifests its effect on NF-kappaB and NF-kappaB-regulated gene expression. Screening of 20 different analogs of curcumin showed that curcumin was the most potent analog in suppressing the tumor necrosis factor (TNF)-induced NF-kappaB activation. Curcumin inhibited TNF-induced NF-kappaB-dependent reporter gene expression in a dose-dependent manner. Curcumin also suppressed NF-kappaB reporter activity induced by tumor necrosis factor receptor (TNFR)1, TNFR2, NF-kappaB-inducing kinase, IkappaB kinase complex (IKK), and the p65 subunit of NF-kappaB. Such TNF-induced NF-kappaB-regulated gene products involved in cellular proliferation [cyclooxygenase-2 (COX-2), cyclin D1, and c-myc], antiapoptosis [inhibitor of apoptosis protein (IAP)1, IAP2, X-chromosome-linked IAP, Bcl-2, Bcl-x(L), Bfl-1/A1, TNF receptor-associated factor 1, and cellular Fas-associated death domain protein-like interleukin-1beta-converting enzyme inhibitory protein-like inhibitory protein], and metastasis (vascular endothelial growth factor, matrix metalloproteinase-9, and intercellular adhesion molecule-1) were also down-regulated by curcumin. COX-2 promoter activity induced by TNF was abrogated by curcumin. We found that curcumin suppressed TNF-induced nuclear translocation of p65, which corresponded with the sequential suppression of IkappaBalpha kinase activity, IkappaBalpha phosphorylation, IkappaBalpha degradation, p65 phosphorylation, p65 nuclear translocation, and p65 acetylation. Curcumin also inhibited TNF-induced Akt activation and its association with IKK. Glutathione and dithiothreitol reversed the effect of curcumin on TNF-induced NF-kappaB activation. Overall, our results indicated that curcumin inhibits NF-kappaB activation and NF-kappaB-regulated gene expression through inhibition of IKK and Akt activation.

Topics: Apoptosis; Base Sequence; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Curcumin; DNA Primers; Down-Regulation; Electrophoretic Mobility Shift Assay; Enzyme Activation; Genes, Reporter; Humans; I-kappa B Kinase; Immunohistochemistry; Neoplasm Metastasis; NF-kappa B; Phosphorylation; Protein Transport; Proto-Oncogene Proteins c-akt

Treatment of highly metastatic murine melanoma cells B16F10 with curcumin (15 microM) for 15 days significantly inhibited matrixmetalloproteinase-2 (MMP-2) activity. Expression of membrane type-1 matrix metalloproteinase (MT1-MMP) and focal adhesion kinase (FAK), an important component of the intracellular signalling pathway, were also reduced to almost background levels. MMP-2, MT1-MMP and FAK did not return to control levels even after 28 days of drug withdrawal. However, effect of curcumin on ligand binding property of integrin receptors was reversible. Downregulation of FAK (which would impair integrin mediated signal transduction cascade) and reduction of MMP-2 activity could be important reasons for anti-metastatic property of curcumin.

Topics: Animals; Antineoplastic Agents; Curcumin; Down-Regulation; Focal Adhesion Kinase 1; Focal Adhesion Protein-Tyrosine Kinases; Integrins; Matrix Metalloproteinase 2; Melanoma; Mice; Neoplasm Metastasis; Protein-Tyrosine Kinases; Signal Transduction; Skin Neoplasms; Tumor Cells, Cultured

Increased expression of proinflammatory and proangiogenic factors are associated with aggressive tumor growth and decreased survival of patients with head and neck squamous cell carcinoma (HNSCC). In as much as genes that are regulated by nuclear factor NF-kappaB suppress apoptosis, induce proliferation, and mediate inflammation, angiogenesis and tumor metastasis, agents that suppress NF-kappaB activation have potential as treatment for various cancers including HNSCC. We demonstrate that all HNSCC cell lines expressed constitutively active NF-kappaB and IkappaBalpha kinase (IKK), which is needed for NF-kappaB activation. Treatment of MDA 686LN cells with curcumin (diferuloylmethane), a pharmacologically safe chemopreventive agent, inhibited NF-kappaB activation through abrogation of IKK. As a result expression of various cell survival and cell proliferative genes including Bcl-2, cyclin D1, IL-6, COX-2 and MMP-9 was suppressed. This, in turn, inhibits proliferation of all HNSCC cell lines, arrests cell cycle in G1/S phase (MDA 686LN) and induces apoptosis as indicated by upstream and downstream caspase activation, PARP cleavage, annexin V staining in MDA 686LN cells. Suppression of NF-kappaB by cell-permeable p65-based peptide and NBD peptide also inhibited the proliferation and induced apoptosis in these cells. Our results indicate that curcumin is a potent inhibitor of cell proliferation and an inducer of apoptosis in HNSCC through suppression of IKK-mediated NF-kappaB activation and of NF-kappaB-regulated gene expression.

Topics: Animals; Antibodies; Antineoplastic Agents; Apoptosis; Carcinoma, Squamous Cell; Caspases; Cell Division; Cell Survival; Curcumin; Gene Expression Regulation, Neoplastic; Head and Neck Neoplasms; Humans; I-kappa B Kinase; Neoplasm Metastasis; NF-kappa B; Protein Serine-Threonine Kinases; Rabbits; Signal Transduction; Tumor Cells, Cultured

The inhibitory effects of curcumin and catechin on lung metastasis induced by B16F-10 melanoma cells were studied in female C57BL/6 mice. Curcumin and catechin significantly (P < 0.001) inhibited lung tumour formation (89.3% and 82.2%, respectively) and significantly increased the life span (143.9% and 80.8%, respectively). Moreover, lung collagen hydroxyproline and serum sialic acid levels were found to be significantly (P < 0.001) lower in treated animals compared to the untreated controls. Curcumin and catechin treatment (10 microg/ml) significantly inhibited the invasion of B16F-10 melanoma cells across the collagen matrix of the Boyden chamber. Gelatin zymographic analysis of the trypsin-activated B16F-10 melanoma cells sonicate revealed that curcumin- and catechin-treated zymograms did not show any metalloproteinase activity. Curcumin and catechin treatment did not inhibit the motility of B16F-10 melanoma cells across a polycarbonate filter in vitro. These findings suggest that curcumin and catechin inhibit the invasion of B16F-10 melanoma cells by inhibition of metalloproteinases, thereby inhibiting lung metastasis.

Topics: Animals; Antineoplastic Agents; Catechin; Cell Adhesion; Cell Movement; Collagen; Curcumin; Female; Gelatin; Hydroxyproline; Lung Neoplasms; Melanoma, Experimental; Mice; Mice, Inbred C57BL; N-Acetylneuraminic Acid; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Transplantation; Survival Rate; Tumor Cells, Cultured

Several polyphenolic compounds were tested for the inhibition of lung metastasis induced by B16F10 melanoma cells in mice. Oral administration of polyphenols such as curcumin and catechin at concentrations of 200 nmol/kg body weight were found to inhibit the lung metastasis maximally as seen by the reduction in the number of lung tumor nodules (80%). Other polyphenols which inhibited the lung tumor nodule formation were rutin (71.2%), epicatechin (61%), naringin (27.2%) and naringenin (26.1%). The polyphenols which did not inhibit lung tumor nodule formation were quercetin, morin and ellagic acid. Consequent to the inhibition of the lung tumor nodules, the life span of animals treated with polyphenols was also found to be increased. Curcumin (143.85%), catechin (80.81%) and rutin (63.59%) had maximal increase in life span. The results indicate a possible use of these compounds in arresting the metastatic growth of tumor cells.

Topics: Animals; Catechin; Cell Survival; Curcumin; Female; Flavonoids; Lung Neoplasms; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Phenols; Polymers; Rutin; Survival Analysis