curcumin and Adenocarcinoma

Lung cancer is a prominent cause of cancer-associated mortality worldwide. The main reason for high mortality due to lung cancer is attributable to the fact that the diagnosis is generally made when it has spread beyond a curable stage and cannot be treated surgically or with radiation therapy. Therefore, new approaches like dietary modifications could be extremely useful in reducing lung cancer incidences. Several fruits and vegetables offer a variety of bioactive compounds to afford protection against several diseases, including lung cancer. A number of research studies involving dietary agents provide strong evidence for their role in the prevention and treatment of lung cancer, and have identified their molecular mechanisms of action and potential targets. In this review article, we summarize data from in-vitro and in-vivo studies and where available, in clinical trials, on the effects of some of the most promising dietary agents against lung cancer.

Topics: Adenocarcinoma; Administration, Oral; Animals; Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Catechin; Curcumin; Flavonoids; Flavonols; Humans; Indoles; Isothiocyanates; Lung Neoplasms; Plant Extracts; Polyphenols

Pancreatic cancer is the fourth leading cause of cancer mortality among both men and women in the United States with a 5-year survival rate of only 4%. Several dietary factors may influence the risk of developing pancreatic cancer and its recurrence. Some of these factors may offer innovative therapies for prevention of this disease. The goal of this review is to provide an overview of pancreatic cancer, as well as current knowledge on the epidemiological, in vitro, in vivo, and clinical studies conducted about this disease using various dietary agents. The main focus is on food-based approaches for preventing this disease particularly, citrus fruits, and foods containing flavonoids, curcumin, folate and vitamin D.

Topics: Adenocarcinoma; Citrus; Curcumin; Diet; Feeding Behavior; Flavonoids; Folic Acid; Food; Humans; Pancreatic Neoplasms; Risk Factors; United States; Vitamin D

Accumulating data clearly indicate that induction of apoptosis is an important event for chemoprevention of cancer by naturally occurring dietary agents. In mammalian cells, apoptosis has been divided into two major pathways: the extrinsic pathway, activated by pro-apoptotic receptor signals at the cellular surface; and the intrinsic pathway, which involves the disruption of mitochondrial membrane integrity. This process is strictly controlled in response to integrity of pro-death signaling and plays critical roles in development, maintenance of homeostasis, and host defense in multicellular organisms. For chemoprevention studies, prostate cancer (PCa) represents an ideal disease due to its long latency, its high incidence, tumor marker availability, and identifiable preneoplastic lesions and risk groups. In this article, we highlight the studies of various apoptosis-inducing dietary compounds for prevention of PCa in vitro in cell culture, in preclinical studies in animals, and in human clinical trials.

Topics: Adenocarcinoma; Aged; Animals; Apoptosis; Carotenoids; Catechin; Clinical Trials as Topic; Curcumin; Drug Screening Assays, Antitumor; Flavonoids; Flavonols; Genistein; Humans; Lycopene; Lythraceae; Male; Mice; Mice, Nude; Mice, Transgenic; Middle Aged; Neoplasm Proteins; Pentacyclic Triterpenes; Phytotherapy; Plant Extracts; Prostatic Neoplasms; Resveratrol; Stilbenes; Tumor Cells, Cultured

Colorectal cancer, the second most frequent diagnosed cancer in the US, causes significant morbidity and mortality in humans. Over the past several years, the molecular and biochemical pathways that influence the development of colon cancer have been extensively characterized. Since the development of colon cancer involves multi-step events, the available drug therapies for colorectal cancer are largely ineffective. The radiotherapy, photodynamic therapy, and chemotherapy are associated with severe side effects and offer no firm expectation for a cure. Thus, there is a constant need for the investigation of other potentially useful options. One of the widely sought approaches is cancer chemoprevention that uses natural agents to reverse or inhibit the malignant transformation of colon cancer cells and to prevent invasion and metastasis. Curcumin (diferuloylmethane), a natural plant product, possesses such chemopreventive activity that targets multiple signalling pathways in the prevention of colon cancer development.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; beta Catenin; Cell Adhesion; Chemoprevention; Colonic Neoplasms; Curcumin; Cytoskeletal Proteins; Humans; Trans-Activators; Transcriptional Activation

Favorable phase I results justified this pilot phase II study to assess the efficacy of docetaxel/curcumin in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (CRPC).. Thirty patients with progressing CRPC and a rising prostate-specific antigen (PSA) received docetaxel/prednisone in standard conditions for 6 cycles in combination with per os curcumin, 6,000 mg/day (day -4 to day +2 of docetaxel). The co-primary endpoint was the overall response rate determined by PSA and target assessments. An ancillary study assessed the seric values of chromogranin A (CgA) and neuron-specific enolase (NSE).. Twenty-six patients received the scheduled treatment, 2 progressed and 2 died before the end of treatment. A PSA response was observed in 59% of patients (14% of PSA normalization) and achieved within the first three cycles for 88% of responders. Partial response was reached for 40% of evaluable patients. The regimen was well tolerated, and no adverse event was attributed to curcumin. Twenty patients were 100% curcumin compliant. The PSA level and objective response rate were not correlated with the serum values of CgA and NSE.. This study produced additional data on curcumin as a treatment for cancer, with a high response rate, good tolerability and patient acceptability, justifying the interest to conduct a randomized trial.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chromogranin A; Curcumin; Docetaxel; Geriatric Assessment; Humans; Male; Medication Adherence; Middle Aged; Phosphopyruvate Hydratase; Pilot Projects; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Survival Rate; Taxoids; Treatment Outcome

Curcumin, a plant-derived natural polyphenol, could be a promising anti-cancer drug and shows synergic effects with cytotoxic agents. We evaluated the safety and feasibility of combination therapy using curcumin with gemcitabine-based chemotherapy.. Gemcitabine-resistant patients with pancreatic cancer received 8 g oral curcumin daily in combination with gemcitabine-based chemotherapy. The primary endpoint was safety for phase I and feasibility of oral curcumin for phase II study.. Twenty-one patients were enrolled. No dose-limiting toxicities were observed in the phase I study and oral curcumin 8 g/day was selected as the recommended dose for the phase II study. No patients were withdrawn from this study because of the intolerability of curcumin, which met the primary endpoint of the phase II study, and the median compliance rate of oral curcumin was 100% (Range 79-100%). Median survival time after initiation of curcumin was 161 days (95% confidence interval 109-223 days) and 1-year survival rate was 19% (4.4-41.4%). Plasma curcumin levels ranged from 29 to 412 ng/ml in five patients tested.. Combination therapy using 8 g oral curcumin daily with gemcitabine-based chemotherapy was safe and feasible in patients with pancreatic cancer and warrants further investigation into its efficacy.

Topics: Adenocarcinoma; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Curcumin; Deoxycytidine; Drug Combinations; Drug Resistance, Neoplasm; Drug Synergism; Female; Gemcitabine; Humans; Male; Medication Adherence; Middle Aged; Oxonic Acid; Pancreatic Neoplasms; Survival Rate; Tegafur

Curcumin has a potent antiproliferative activity and can also potentiate the antitumor effect of gemcitabine. This study was undertaken to evaluate the activity and feasibility of gemcitabine in combination with curcumin in patients with advanced pancreatic cancer. Seventeen patients were enrolled in the study and received 8,000 mg of curcumin by mouth daily, concurrently with gemcitabine 1,000 mg/m(2) IV weekly × 3 of 4 wk; 5 patients (29%) discontinued curcumin after a few days to 2 wk due to intractable abdominal fullness or pain, and the dose of curcumin was reduced to 4,000 mg/day because of abdominal complaints in 2 other patients. One of 11 evaluable patients (9%) had partial response, 4 (36%) had stable disease, and 6 (55%) had tumor progression. Time to tumor progression was 1-12 mo (median 2½), and overall survival was 1-24 mo (median 5). Low compliance for curcumin at a dose of 8,000 mg/day, when taken together with systemic gemcitabine, may prevent the use of high doses of oral curcumin needed to achieve systemic effect. Further studies should be conducted to evaluate the ability of other formulations of curcumin to enhance the effect of chemotherapy in cancer patients.

Topics: Adenocarcinoma; Aged; Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Curcumin; Deoxycytidine; Disease Progression; Feasibility Studies; Female; Gemcitabine; Humans; Male; Medication Adherence; Middle Aged; Pancreatic Neoplasms; Severity of Illness Index; Survival Analysis

Pancreatic cancer is almost always lethal, and the only U.S. Food and Drug Administration-approved therapies for it, gemcitabine and erlotinib, produce objective responses in <10% of patients. We evaluated the clinical biological effects of curcumin (diferuloylmethane), a plant-derived dietary ingredient with potent nuclear factor-kappaB (NF-kappaB) and tumor inhibitory properties, against advanced pancreatic cancer.. Patients received 8 g curcumin by mouth daily until disease progression, with restaging every 2 months. Serum cytokine levels for interleukin (IL)-6, IL-8, IL-10, and IL-1 receptor antagonists and peripheral blood mononuclear cell expression of NF-kappaB and cyclooxygenase-2 were monitored.. Twenty-five patients were enrolled, with 21 evaluable for response. Circulating curcumin was detectable as drug in glucuronide and sulfate conjugate forms, albeit at low steady-state levels, suggesting poor oral bioavailability. Two patients showed clinical biological activity. One had ongoing stable disease for >18 months; interestingly, one additional patient had a brief, but marked, tumor regression (73%) accompanied by significant increases (4- to 35-fold) in serum cytokine levels (IL-6, IL-8, IL-10, and IL-1 receptor antagonists). No toxicities were observed. Curcumin down-regulated expression of NF-kappaB, cyclooxygenase-2, and phosphorylated signal transducer and activator of transcription 3 in peripheral blood mononuclear cells from patients (most of whom had baseline levels considerably higher than those found in healthy volunteers). Whereas there was considerable interpatient variation in plasma curcumin levels, drug levels peaked at 22 to 41 ng/mL and remained relatively constant over the first 4 weeks.. Oral curcumin is well tolerated and, despite its limited absorption, has biological activity in some patients with pancreatic cancer.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Curcumin; Cyclooxygenase 2; Cytokines; Electrophoretic Mobility Shift Assay; Female; Humans; Immunohistochemistry; Male; Middle Aged; NF-kappa B; Pancreatic Neoplasms

Probiotic bacteria with functions of importance to the health and well-being of the host exhibit various medicinal properties including anti-proliferative properties against cancer cells. There are observations demonstrating probiotic bacteria and their metabolomics can be different in various populations with different eating habits. Here, Lactobacillus plantarum was treated with curcumin (the major compound of turmeric), and its resistance to the curcumin was determined. After then the cell-free supernatants of untreated bacteria (CFS) and bacteria treated with curcumin (cur-CFS) were isolated and their anti-proliferative properties against HT-29 colon cancer cells were compared. The ability of L. plantarum treated with curcumin to combat a variety of pathogenic bacterial species and its ability to survive in acidic conditions were evidence that the probiotic properties of the bacterium were unaffected by the curcumin treatment. L. plantarum treated with curcumin and intact L. plantarum were both able to live in acidic conditions, according to the results of the resistance to low pH test. The MTT result showed that CFS and cur-CFS dose-dependently decreased the growth of HT29 cells with a half-maximal inhibitory concentration of 181.7 and 116.3 µL/mL at 48 h, respectively. Morphological alteration of DAPI-stained cells also exhibited significant fragmentation in the chromatin within the nucleus of cur-CFS-treated cells compared to CFS-treated HT29 cells. Moreover, flow cytometry analyses of apoptosis and cell cycle confirmed DAPI staining and MTT assay results and stipulated the increased occurrence of programmed cell death (apoptosis) in cur-CFS-treated cells (~ 57.65%) compared to CFS-treated cells (~ 47%). These results were more confirmed with qPCR and exhibited the upregulation of Caspase 9-3 and BAX genes, and downregulation of the BCL-2 gene in cur-CFS- and CFS-treated cells. In conclusion, turmeric spice and curcumin may affect the metabolomics of probiotics in intestinal flora which could subsequently influence their anticancer properties.

Topics: Adenocarcinoma; Apoptosis; Colonic Neoplasms; Curcumin; HT29 Cells; Humans; Lactobacillus plantarum

Artemisinin, curcumin or quercetin, alone or in combination, were loaded in nutriosomes, special phospholipid vesicles enriched with Nutriose FM06®, a soluble dextrin with prebiotic activity, that makes these vesicles suitable for oral delivery. The resulting nutriosomes were sized between 93 and 146 nm, homogeneously dispersed, and had slightly negative zeta potential (around -8 mV). To improve their shelf life and storability over time, vesicle dispersions were freeze-dried and stored at 25 °C. Results confirmed that their main physico-chemical characteristics remained unchanged over a period of 12 months. Additionally, their size and polydispersity index did not undergo any significant variation after dilution with solutions at different pHs (1.2 and 7.0) and high ionic strength, mimicking the harsh conditions of the stomach and intestine. An in vitro study disclosed the delayed release of curcumin and quercetin from nutriosomes (∼53% at 48 h) while artemisinin was quickly released (∼100% at 48 h). Cytotoxicity assays using human colon adenocarcinoma cells (Caco-2) and human umbilical vein endothelial cells (HUVECs) proved the high biocompatibility of the prepared formulations. Finally, in vitro antimalarial activity tests, assessed against the 3D7 strain of Plasmodium falciparum, confirmed the effectiveness of nutriosomes in the delivery of curcumin and quercetin, which can be used as adjuvants in the antimalaria treatment. The efficacy of artemisinin was also confirmed but not improved. Overall results proved the possible use of these formulations as an accompanying treatment of malaria infections.

Topics: Adenocarcinoma; Adjuvants, Immunologic; Adjuvants, Pharmaceutic; Antimalarials; Artemisinins; Caco-2 Cells; Colonic Neoplasms; Curcumin; Endothelial Cells; Humans; Liposomes; Malaria; Quercetin

Curcumin; the major polyphenolic compound, isolated from

Topics: Adenocarcinoma; Antioxidants; Caco-2 Cells; Colonic Neoplasms; Curcumin; Estrogen Receptor alpha; Estrogen Receptor beta; Humans; Povidone; Receptors, Estrogen; Thiobarbituric Acid Reactive Substances

Pancreatic adenocarcinoma is by far the deadliest type of cancer. Inflammation is one of the important risk factors in tumor development. However, it is not yet clear whether deterioration in pancreatic cancer patients is related to inflammation, as well as the underlying mechanism. In addition, JNK is abnormally activated in pancreatic cancer cells and the JNK inhibitor C66 reduces the inflammatory microenvironment in the tumor. Therefore, the aim of this study was to evaluate the role of C66 in the proliferation and migration of pancreatic cancer. Our results showed that various inflammatory cytokines, such as IL-1β, IL-6, IL-8, and IL-15, were more expressed in pancreatic cancer than in the matching normal tissue. Furthermore, C66, a curcumin analogue with good anti-inflammatory activity, inhibited the proliferation and migration of pancreatic cancer cells in a dose-dependent manner, and effectively inhibited the expression of the above inflammatory factors. Our previous research demonstrated that C66 prevents the inflammatory response by targeting JNK. Therefore, in this study, JNK activity in pancreatic cancer cells was investigated, revealing that JNK was highly activated, and the treatment with C66 inhibited the phosphorylation of JNK. Next, shJNK was used to knockdown JNK expression in pancreatic cancer cells to further confirm the role of JNK in the proliferation and migration of this tumor, as well as in the inflammatory tumor microenvironment (TME). The results demonstrated that JNK knockdown could significantly inhibit the proliferation and migration of pancreatic cancer. Moreover, the low JNK expression in pancreatic cancer cells significantly inhibited the expression of various inflammatory factors. These results indicated that C66 inhibited the progression of pancreatic cancer through the inhibition of JNK-mediated inflammation.

Topics: Adenocarcinoma; Animals; Curcumin; Humans; Inflammation; JNK Mitogen-Activated Protein Kinases; Mice; Mice, Inbred C57BL; Pancreatic Neoplasms; Tumor Microenvironment

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

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

Curcumin has anti-oxidant, anti-cancer and anti-carcinogen property. Our laboratory had previously reported that, curcumin treatment induces reactive oxygen species (ROS) generation in HT-29 cell line, an effect contradictory to its anti-oxidant property. This study evaluates the role of p53 in curcumin mediated ROS generation and cell death. Curcumin induced ROS was determined by 2',7'-dichlorofluorescein and apoptosis by Hoechst33342/PI staining in HT-29 and HCT-116 cell lines. ROS generation occurs within 1 hour of 40 µM curcumin treatment and a reduction was observed by third hour in HCT-116 insinuating p53 involvement. N-acetyl cysteine (NAC) pre-treatment effectively quenched ROS and inhibited membrane potential loss in HT-29, but less effective in HCT-116. Mitochondrial membrane potential loss is evident with 10 and 40 µM curcumin in HCT-116 and at 40 µM curcumin in HT-29. Total p53 protein level increase was observed by 24 hours in HCT-116 upon NAC pre-treatment. Our results indicate that curcumin induces ROS mediated cell death in colon adenocarcinoma cell lines and may be mediated via p53.

Topics: Adenocarcinoma; Apoptosis; Colonic Neoplasms; Curcumin; HCT116 Cells; HT29 Cells; Humans; Mutation; Oxidative Stress; Tumor Suppressor Protein p53

The p53, tumor suppressor protein is inactivated upon mutation in the DNA-binding domain and the non-functional protein leads to cancers. The p53Y220C is one of the most frequently observed mutations in p53 with a scope of rescuing the protein function using small molecules.. Using computational modeling, biophysical, and experimental cell-based studies we tried to understand the molecular basis of Curcumin as a potential small molecule to stabilize p53Y220C mutant and restore its function. The pancreatic adenocarcinomas BxPC-3 p53Y220C mutant cell line was used for cell-based assays to determine the therapeutic potential of Curcumin to restore mutant p53 to function like wild type.. The study indicated that the natural compound Curcumin could rescue mutant p53Y220C in BxPC-3 pancreatic adenocarcinomas cell line to function like wild-type and activate apoptotic pathways.

Topics: Adenocarcinoma; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Curcumin; Humans; Molecular Docking Simulation; Pancreatic Neoplasms; Point Mutation; Tumor Suppressor Protein p53

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

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

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

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

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

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

Gastric cancer (GC) is one of the prevalent human malignancies and the third most common cause of cancer-related death worldwide. The doxorubicin hydrochloride is one of the important chemotherapeutic anticancer agents, with a limited therapeutic efficacy for treatment of GC. Therefore, taking advantage of synergistic effects by strategies like combination therapy seems appropriate and promising in treatment of GC. The aim of this study was to investigate a novel method to enhance the therapeutic efficacy of doxorubicin (as a chemotherapeutic agent) by co-administration of curcumin (as a bioactive herbal compound) in GC treatment. In the present study, the effects of curcumin, doxorubicin, and their combinations (Dox-Cur) were evaluated on the viability, morphological features, tumor spheroid formation, migration, invasion, and apoptosis of gastric adenocarcinoma cell line (AGS). Moreover, expression levels of BAX, BCL-2, and CASP9 genes were assessed among AGS cells treated with curcumin, doxorubicin, and Dox-Cur. The obtained results showed that all of curcumin, doxorubicin, and Dox-Cur treatments significantly decreased the viability, tumor spheroid formation, migration, and invasion in the GC model cells. Furthermore, apoptosis rates in AGS cells were increased in a concentration- and time-dependent manner in all of the treatment groups. Moreover, the anticancer activity of the Dox-Cur combination was significantly more than curcumin and doxorubicin treatments alone. According to the results, Dox-Cur combination therapy exerts more profound apoptotic and anticancer effects on the AGS cell line than curcumin or doxorubicin monotherapy.

Topics: Adenocarcinoma; Antineoplastic Agents, Phytogenic; Apoptosis; bcl-2-Associated X Protein; Caspase 9; Cell Line, Tumor; Cell Movement; Cell Survival; Curcuma; Curcumin; Doxorubicin; Drug Resistance, Neoplasm; Drug Synergism; Gene Expression Regulation, Neoplastic; Humans; Plant Extracts; Proto-Oncogene Proteins c-bcl-2; Spheroids, Cellular; Stomach Neoplasms

Enhancer of zeste homolog 2 (EZH2), an oncogene, is a commonly up-regulated epigenetic factor in human cancer. Hepatocellular carcinoma deletion gene 1 (DLC1) is an antioncogene that is either expressed at low levels or not expressed in many malignant tumours. Curcumin is a promising anticancer drug that has antitumour effects in many tumours, but its mechanism of action is unclear. Our research demonstrated that EZH2 was up-regulated in breast cancer (BC) tissues and cells, whereas DLC1 was down-regulated, and the expression of EZH2 and DLC1 was negatively correlated in BC. By analysing the characteristics of clinical cases, we found that positive expression of EZH2 and negative expression of DLC1 may be predictors of poor prognosis in patients with triple-negative breast cancer (TNBC). Moreover, knockdown of EZH2 expression restored the expression of DLC1 and inhibited the migration, invasion and proliferation, promoted the apoptosis, and blocked the cell cycle of MDA-MB-231 cells. Furthermore, we found that curcumin restored the expression of DLC1 by inhibiting EZH2; it also inhibited the migration, invasion and proliferation of MDA-MB-231 cells, promoted their apoptosis and blocked the cell cycle. Finally, xenograft tumour models were used to demonstrate that curcumin restored DLC1 expression by inhibiting EZH2 and also inhibited the growth and promoted the apoptosis of TNBC cells. In conclusion, our results suggest that curcumin can inhibit the migration, invasion and proliferation, promote the apoptosis, block the cycle of TNBC cells and restore the expression of DLC1 by inhibiting the expression of EZH2.

Topics: Adenocarcinoma; Adult; Aged; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Cycle; Cell Division; Cell Line, Tumor; Cell Movement; Curcumin; Enhancer of Zeste Homolog 2 Protein; Female; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; GTPase-Activating Proteins; Histone Code; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Neoplasm Invasiveness; Neoplasm Proteins; Prognosis; RNA, Small Interfering; Triple Negative Breast Neoplasms; Tumor Suppressor Proteins; Xenograft Model Antitumor Assays

Pancreatic adenocarcinoma (PDAC) is one of the most fatal malignancies. Surgical resection supplemented by chemotherapy remains the major therapeutic regimen, but with unavoidable resistance and systemic toxic reaction. Curcumin is a known safe natural compound that can effectively eliminate pancreatic adenocarcinoma cells in vitro, making it a promising candidate for substitution in subsequent chemotherapy. However, due to its extremely low bioavailability caused by its insolubility and circular elimination, curcumin had an unexpectedly modest therapeutic effect in clinical trials.. Here, we electrospun curcumin/gelatin-blended nanofibrous mat to largely improve curcumin's bioavailability by local controlled-release. With characterization by scanning electron microscopy, fluorescence microscopy, Fourier transform infrared spectroscopy, X-ray diffraction and high-performance liquid chromatography, it was revealed that curcumin was uniformly dispersed in the fiber of the mats with nanoscopic dimensions and could be continuously released into the surrounding medium for days. The cancer inhibitory effects of nano-curcumin and underlying mechanisms were further explored by assays using pancreatic adenocarcinoma cell and experiments using xenograft model. The results showed the released nano-curcumin could effectively inhibit pancreatic adenocarcinoma cell proliferation not only in vitro, but more importantly in vivo. This cytotoxic effect of nano-curcumin against pancreatic adenocarcinoma was achieved through provoking the production of intracellular reactive oxygen species and activating endoplasmic reticulum stress, which leads to enhanced cell apoptosis via decreased phosphorylation of signal transducer and activator of transcription 3.. Clinically, curcumin/gelatin-blended nanofibrous mat could be a promising, secure, efficient and affordable substitutional agent for the elimination of residual cancer cells after tumor resection. Moreover, our strategy to obtain curcumin released from nanofibrous mat may provide a universally applicable approach for the study of the therapeutic effects and molecular mechanisms of other potential medicines with low bioavailability.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Apoptosis; Biological Availability; Cell Line, Tumor; Cell Proliferation; Curcumin; Endoplasmic Reticulum Stress; Gelatin; Humans; Mice; Nanofibers; Pancreatic Neoplasms; Reactive Oxygen Species; X-Ray Diffraction; Xenograft Model Antitumor Assays

Cancer cells require higher levels of ATP for their sustained growth, proliferation, and chemoresistance. Mitochondrial matrix protein, C1qbp is upregulated in colon cancer cell lines. It protects the mitochondria from oxidative stress, by inhibiting the Membrane Permeability Transition (MPT) pore and providing uninterrupted synthesis of ATP. This intracellular interaction of C1qbp could be involved in chemoresistance development. Natural chemosensitizing agent, curcumin has been used in the treatment of multiple cancers. In this current study, we elucidate the role of C1qbp during curcumin induced chemosensitization to doxorubicin resistant colon cancer cells. The possible interaction between C1qbp and curcumin was determined using bioinformatics tools-AutoDock, SYBYL, and PyMol. Intracellular doxorubicin accumulation by fluorimetry and dead cell count was carried out to determine development of chemoresistance. Effect of curcumin treatment and cytotoxicity was measured by MTT and lactate dehydrogenase release. Morphological analysis by phase contrast microscopy and colony forming ability by colonogenic assay were also performed. In addition, Cox-2 could mediate P-glycoprotein upregulation via phosphorylation of c-Jun. Thus, the gene level expression of P-glycoprotein and Cox-2 was also investigated using PCR. Through molecular docking we identified possible interaction between curcumin and C1qbp. We observed development of chemoresistance upon 6th day treatment. Concentration dependent alleviation of chemoresistance development by curcumin was confirmed and was found to reduce gene level expression of P-glycoprotein and Cox-2. Hence, curcumin could interact directly with C1qbp protein and this interaction could contribute to the chemosensiting effect to doxorubicin in colon cancer cells.

Topics: Adenocarcinoma; Colonic Neoplasms; Curcumin; Doxorubicin; Drug Resistance, Neoplasm; HT29 Cells; Humans; Neoplasm Proteins

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

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

BACKGROUND Curcumin is a polyphenol compound extracted from the root of the herb Curcuma longa, which is used in traditional Chinese medicine (TCM). Worldwide, colorectal carcinoma (CRC) is an increasing cause of morbidity and mortality. This study aimed to investigate the effects of increasing concentrations of curcumin on cell viability, proliferation, and apoptosis of SW620 human colonic adenocarcinoma cells cultured in vitro, and the signaling pathways involved. MATERIAL AND METHODS SW620 human colonic adenocarcinoma cells were cultured in curcumin at concentrations of 0, 4, 8, 16, and 32 μmol/l for 48 hours. Specific small interfering RNA (siRNA) was transfected into SW620 cells to silence the expression of caudal type homeobox-2 (CDX2). Cell viability was measured using the MTT assay. Flow cytometry evaluated cell apoptosis. Western blot and reverse transcriptase-polymerase chain reaction (RT-PCR) were used to assess the nuclear translocation of b-catenin and the activation of Wnt signaling. RESULTS Curcumin reduced cell viability and increased apoptosis of SW620 human colonic adenocarcinoma cells in a dose-dependent way, and increased the expression of CDX2 but decreased ß-catenin nuclear translocation and the expression of Wnt3a, c-Myc, survivin, and cyclin D1. CDX2 silencing significantly reduced the effects of curcumin on SW620 human colonic adenocarcinoma cells. The nuclear translocation of ß-catenin, and expression levels of Wnt3a, c-Myc, survivin, and cyclin D1 were significantly higher in CDX2-silenced SW620 cells. CONCLUSIONS Curcumin reduced cell viability and increased apoptosis in SW620 human colonic adenocarcinoma cells by restoring CDX2, which inhibited the Wnt/ß-catenin signaling pathway.

Topics: Adenocarcinoma; Apoptosis; beta Catenin; CDX2 Transcription Factor; Cell Line, Tumor; Cell Proliferation; Cell Survival; Colonic Neoplasms; Curcumin; Dose-Response Relationship, Drug; Humans; Wnt Signaling Pathway

Pancreatic cancer is one of the most malignant cancers with a high mortality rate. Some types of pancreatic cancer cells overexpress epidermal growth factor receptor (EGFR), which is a potential target for anticancer agents. In this study, we examined the effect of epidermal growth factor (EGF)-conjugated liposomes containing curcumin (EGF-LP-Cur) on three different EGFR-expressed human pancreatic cancer cell lines, BxPC-3, Panc-1 and Mia Paca-2. We have demonstrated that it is feasible to prepare liposomal vesicles of EGF-LP-Cur and that it is stable in the liquid vehicle at ambient conditions for three weeks. In addition, the formulation of curcumin had higher cytotoxicity on BxPC-3 than on any other cells. It is also shown that the cellular uptake of curcumin on BxPC-3, which is essential for the cytotoxicity, is associated with EGFR-mediated mechanism of action. In summary, our results have showed that targeting EGFR with EGF-conjugated curcumin liposomes enhanced the antitumor activity of curcumin against human pancreatic cancer cells.

Topics: Adenocarcinoma; Antineoplastic Agents; Curcumin; Epidermal Growth Factor; Humans; Liposomes; Pancreatic Neoplasms

Nanoscale drug delivery systems have emerged as promising alternatives to overcome the problems associated with by conventional chemotherapy for cancer treatment such as poor drug stability and bio-distribution. Herein, we report a single walled carbon nanotubes (SWCNTs) based drug delivery system functionalized with polysaccharides such as alginate (ALG) and chitosan (CHI), which can be loaded with an anticancer drug curcumin (CUR). Modification of SWCNTs renders high drug loading efficiency and sustained drug release, imperative for drug activity. These were characterized through various tools viz, microscopic (transmission electron microscopy, scanning electron microscopy and atomic force microscopy) and zeta potential analysis. Incorporation of CUR inside the modified SWCNTs was studied through Fourier transform infrared spectroscopy, fluorescence and UV-visible spectroscopy. In vitro release studies were conducted to gain an insight into the pH-dependent release behavior of the entrapped CUR from modified SWCNTs. The anti-cancer potential was further demonstrated using human lung adenocarcinoma (A549) cells as a model system. Various cell culture based assays were performed to study the ability of released CUR from modified SWCNTs for inhibiting the cancer cell proliferation by inducing apoptosis.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Antineoplastic Agents; Curcumin; Drug Carriers; Drug Delivery Systems; Humans; Lung Neoplasms; Nanotubes, Carbon; Tumor Cells, Cultured

Curcumin is a natural dietary polyphenol compound that has various pharmacological activities such as antiproliferative and cancer-preventive activities on tumor cells. Indeed, the role reactive oxygen species (ROS) generated by curcumin on cell death and cell proliferation inhibition in colon cancer is poorly understood. In the present study, we hypothesized that curcumin-induced ROS may promote apoptosis and cell cycle arrest in colon cancer. To test this hypothesis, the apoptosis-inducing potential and cell cycle inhibition effect of ROS induced by curcumin was investigated in Smd4 and p53 mutated HT-29 colon adenocarcinoma cells. We found that curcumin treatment significantly increased the level of ROS in HT-29 cells in a dose- and time-dependent manner. Furthermore, curcumin treatment markedly decreased the cell viability and proliferation potential of HT-29 cells in a dose- and time-dependent manner. Conversely, generation of ROS and inhibitory effect of curcumin on HT-29 cells were abrogated by N-acetylcysteine treatment. In addition, curcumin treatment did not show any cytotoxic effects on HT-29 cells. Furthermore, curcumin-induced ROS generation caused the DNA fragmentation, chromatin condensation, and cell nuclear shrinkage and significantly increased apoptotic cells in a dose- and time-dependent manner in HT-29 cells. However, pretreatment of N-acetylcysteine inhibited the apoptosis-triggering effect of curcumin-induced ROS in HT-29 cells. In addition, curcumin-induced ROS effectively mediated cell cycle inhibition in HT-29 cells. In conclusion, our data provide the first evidence that curcumin induces ROS independent apoptosis and cell cycle arrest in colon cancer cells that carry mutation on Smad4 and p53.

Topics: Adenocarcinoma; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Cycle Checkpoints; Cell Survival; Colon; Colonic Neoplasms; Curcuma; Curcumin; HT29 Cells; Humans; Mitochondria; Mutation; Phytotherapy; Plant Extracts; Reactive Oxygen Species; Smad4 Protein; Tumor Suppressor Protein p53

Curcumin, a natural polyphenolic compound isolated from the plant

Topics: A549 Cells; Adenocarcinoma; Adenocarcinoma of Lung; Autophagy; Curcumin; Enzyme Induction; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Neoplasm Proteins; Sialyltransferases

Gold NPs have great potential in biomedical applications. PAMAM dendrimers are spherical, hyper branched macromolecules which can encapsulate therapeutic molecules while stabilizing metal nanoparticle such as gold NPs. The aim of the current study was to investigate the theranostic capability of curcumin-loaded dendrimer-gold hybrid structure. Dendrimer-gold hybrid structure was synthesized by complexing AuCl

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Aptamers, Nucleotide; Cell Line, Tumor; CHO Cells; Colonic Neoplasms; Cricetinae; Cricetulus; Curcumin; Dendrimers; Female; Gold; Humans; Metal Nanoparticles; Mice; Mice, Inbred BALB C; Mucin-1; Nanostructures; Polyethylene Glycols; Theranostic Nanomedicine; Tomography, X-Ray Computed

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

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

Curcumin and its chalcone derivatives inhibit the growth of human cancer cells. It is reported that replacement of two OH groups in curcumin with less polar groups like methoxy increases its anti-proliferative activity. In this study, we explored benzylidine cyclohexanone derivatives with non-polar groups, to see if they possess increased anti-cancer activity. Novel 2,6-bis benzylidine cyclohexanone analogues of curcumin were synthesized, and their inhibitory effects on gastric adenocarcinoma (AGS) and esophageal squamous cell carcinoma (KYSE30) cancer cells were studied using an MTT assay. Cell apoptosis was detected by EB/AO staining, and cell cycle was analyzed by flow cytometry. Real-time PCR was performed for gene expression analysis. All synthesized analogues were cytotoxic toward gastric and esophageal cancer cells and showed lower IC

Topics: Adenocarcinoma; Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Curcumin; Cyclohexanones; Esophageal Squamous Cell Carcinoma; Flow Cytometry; Gene Expression Regulation, Neoplastic; Humans; Neoplasm Proteins; Stomach Neoplasms

Curcumin, a dietary supplement or herbal medicine from Curcuma longa, has shown antitumor activity in different cancer cell lines and clinical trials. CA916798, a novel protein, is overexpressed in multidrug-resistant tumor cells. This study aimed to assess the effects of curcumin on regulating chemosensitivity in cisplatin-resistant non-small cell lung cancer (NSCLC) cells in vitro and to explore the underlying molecular mechanisms. Human cisplatin-sensitive A549 and cisplatin-resistant A549/CDDP lung adenocarcinoma cells were treated with curcumin to assess cell viability and gene modulations using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting. CA916798 shRNA and point mutations were used to assess the CA916798 functions and phosphorylation sites. Bisdemethoxycurcumin sensitized cisplatin-resistant lung cancer cells to various chemotherapeutic agents, including cisplatin. Bisdemethoxycurcumin reduced the levels of CA916798 mRNA and protein in A549 and A549/CDDP cells, while it also suppressed phosphatidylinositol-3-kinase (PI3K)/AKT signaling. CA916798, as a downstream gene, interacted with AKT after bisdemethoxycurcumin treatment in A549 and A549/CDDP cells. Moreover, A549/CDDP cells expressing the point-mutated CA916798-S20D protein were more resistant to cisplatin and bisdemethoxycurcumin, whereas tumor cells expressing CA916798-S20A, CA916798-S31A, CA916798-S60A, CA916798-S93A, or CA916798-T97A (different sites of amino acid phosphorylation) showed similar sensitivity or resistance to cisplatin and bisdemethoxycurcumin, compared with the control cells. Bisdemethoxycurcumin is able to sensitize cisplatin-resistant NSCLC cells to chemotherapeutic agents by inhibition of CA916798 and PI3K/AKT activities. Moreover, phosphorylation of CA916798 at the S20 residue plays a critical role in mediating bisdemethoxycurcumin antitumor activity.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Survival; Cisplatin; Curcumin; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Mice; Mice, Nude; Neoplasm Proteins; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases

Barrett's esophagus, a metaplasia resulting from a long-standing reflux disease, and its progression to esophageal adenocarcinoma (EAC) are characterized by activation of pro-inflammatory pathways, induced by cytokines.. An in vitro cell culture system representing the sequence of squamous epithelium (EPC1 and EPC2), Barrett's metaplasia (CP-A), dysplasia (CP-B) to EAC (OE33 and OE19) was used to investigate TNF-α-mediated induction of interleukin-8 (IL-8).. IL-6 and IL-8 expressions are increasing with the progression of Barrett's esophagus, with the highest expression of both cytokines in the dysplastic cell line CP-B. IL-8 expression in EAC cells was approx. 4.4-fold (OE33) and eightfold (OE19) higher in EAC cells than in squamous epithelium cells (EPC1 and EPC2). The pro-inflammatory cytokine TNF-α increased IL-8 expression in a time-, concentration-, and stage-specific manner. Furthermore, TNF-α changed the EMT marker profile in OE33 cells by decreasing the epithelial marker E-cadherin and increasing the mesenchymal marker vimentin. The anti-inflammatory compound curcumin was able to repress proliferation and to activate apoptosis in both EAC cell lines.. The increased basal expression levels of IL-8 with the progression of Barrett's esophagus constrain NFκB activation and its contribution in the manifestation of Barrett's esophagus. An anti-inflammatory compound, such as curcumin, could create an anti-inflammatory microenvironment and thus potentially support an increase chemosensitivity in EAC cells.

Topics: Adenocarcinoma; Anti-Inflammatory Agents, Non-Steroidal; Barrett Esophagus; Cell Line; Curcumin; Disease Progression; Drug Evaluation, Preclinical; Epithelial-Mesenchymal Transition; Esophageal Neoplasms; Humans; Interleukin-6; Interleukin-8; Tumor Necrosis Factor-alpha; Vimentin

Previously we showed that BDMC, an analogue of curcumin suppresses growth of human breast and laryngeal cancer cell line by causing apoptosis. Here, we demonstrate the enhanced anti-cancer activity of a heterocyclic ring (indole) incorporated curcumin analogue ((1E, 6E)-1, 7-di (1H-indol-3-yl) hepta-1, 6-diene-3, 5-Dione), ICA in short, in comparison to curcumin.. ICA was synthesized by a one pot condensation reaction. Anti-cancer potential of ICA was assessed in three human cancer cell lines of different origin (Lung adenocarcinoma (A549), leukemia (K562) and colon cancer (SW480)) by MTT assay. Mode of cell death was determined by acridine orange-ethidium bromide (Ao-Eb) staining. Putative cellular targets of ICA were investigated by molecular docking studies. Cell cycle analysis following curcumin or ICA treatment in SW480 cell line was carried out by flow cytometry. Expression levels of Cyclin D1 and apoptotic markers, such as Caspase 3, 8 and 9 were studied by western blot analysis in SW480 cell line treated with or without ICA and curcumin.. The yield of ICA synthesis was found to be 69% with a purity of 98%. ICA demonstrated promising anti-cancer activity compared to curcumin alone, as discerned by MTT assay. ICA was non-toxic to the cell line of normal origin. We further observed that ICA is ∼2 fold more potent than curcumin in inhibiting the growth of SW480 cells. Ao-Eb staining revealed that ICA could induce apoptosis in all the cell lines tested. Molecular docking studies suggest that ICA may possibly exhibit its anticancer effect by inhibiting EGFR in A549, Bcr-Abl in K562 and GSK-3β kinase in SW480 cell line. Moreover, ICA showed strong binding avidity for Bcl-2 protein in silico, which could result in induction of apoptosis. Cell cycle analysis revealed that both curcumin and ICA induced concomitant cell cycle arrest at G0/G1 and G2/M phase. Western blot shows that ICA could effectively down regulate the expression of cell cycle protein cyclin D1, while promoting the activation of Caspase 3, 8 and 9 when compared to curcumin in human colon cancer cell line SW480.. The result of this study indicates that ICA could hold promise to be a potential anti-cancer agent. Since ICA has shown encouraging results in terms of its anti-cancer activity compared to curcumin, further research is necessary to fully delineate the underlying molecular mechanism of its anticancer potential.

Topics: Adenocarcinoma; Antineoplastic Agents; Apoptosis; Binding Sites; Cell Line, Tumor; Colonic Neoplasms; Computer Simulation; Curcumin; Diarylheptanoids; Gene Expression Regulation; Humans; Indoles; Leukemia; Lung Neoplasms; Models, Biological; Models, Molecular; Molecular Structure; Protein Conformation; Structure-Activity Relationship

Curcumin, a natural polyphenolic compound and it is isolated from the rhizome of Curcuma longa, have been reported to possess anticancer effect against stage I and II colon cancer. However, the effect of curcumin on colon cancer at Dukes' type C metastatic stage III remains still unclear. In the present study, we have investigated the anticancer effects of curcumin on p53 mutated COLO 320DM human colon adenocarcinoma cells derived from Dukes' type C metastatic stage. The cellular viability and proliferation were assessed by trypan blue exclusion assay and MTT assay, respectively. The cytotoxicity effect was examined by lactate dehydrogenase (LDH) cytotoxicity assay. Apoptosis was analyzed by DNA fragmentation analysis, Hoechst and propidium iodide double fluorescent staining and confocal microscopy analysis. Cell cycle distribution was performed by flow cytometry analysis. Here we have observed that curcumin treatment significantly inhibited the cellular viability and proliferation potential of p53 mutated COLO 320DM cells in a dose- and time-dependent manner. In addition, curcumin treatment showed no cytotoxic effects to the COLO 320DM cells. DNA fragmentation analysis, Hoechst and propidium iodide double fluorescent staining and confocal microscopy analysis revealed that curcumin treatment induced apoptosis in COLO 320DM cells. Furthermore, curcumin caused cell cycle arrest at the G1 phase, decreased the cell population in the S phase and induced apoptosis in COLO 320DM colon adenocarcinoma cells. Together, these data suggest that curcumin exerts anticancer effects and induces apoptosis in p53 mutated COLO 320DM human colon adenocarcinoma cells derived from Dukes' type C metastatic stage.

Topics: Adenocarcinoma; Apoptosis; Cell Cycle Checkpoints; Cell Division; Cell Line, Tumor; Cell Proliferation; Cell Survival; Colonic Neoplasms; Curcumin; DNA Fragmentation; G1 Phase Cell Cycle Checkpoints; Humans; Mutation; S Phase; Tumor Suppressor Protein p53

In silico modeling of the polymer-drug nanocarriers have now days became a powerful virtual screening tool for the optimization of new drug delivery systems. The interactions between amorphous chitin nanoparticles (AC-NPs) with three different types of anti-cancer drugs such as curcumin, docetaxel and 5-flurouracil were studied by integration of computational and experimental techniques. The drug entrapment and drug loading efficiency of these three drugs with AC-NPs were (98±1%), (77±2%), and (47±12%), respectively. Further, cytotoxicity and cellular uptake studies of drug loaded AC-NPs on Gastric adenocarcinoma (AGS) cells showed enhanced drug uptake and cancer cell death. In silico binding energy (BE) between AC-NPs with these anti-cancer drugs were studied by molecular docking technique. Computational drug's BEs are in excellent agreement with experimental AC-NPs drug loading (R(2)=0.9323) and drug entrapment (R(2)=0.9741) efficiencies. Thus, present integrated study revealed significant insight on chemical nature, strength, and putative interacting sites of anti-cancer drugs with AC-NPs.

Topics: Adenocarcinoma; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Chitin; Curcumin; Docetaxel; Drug Carriers; Fluorouracil; Humans; Molecular Docking Simulation; Nanoparticles; Stomach; Stomach Neoplasms; Taxoids; Thermodynamics

Pancreatic cancer is a highly aggressive malignancy, which is intrinsically resistant to current chemotherapies. Herein, we investigate whether bisdemethoxycurcumin (BDMC), a derivative of curcumin, potentiates gemcitabine in human pancreatic cancer cells. The result suggests that BDMC sensitizes gemcitabine by inducing mitochondrial dysfunctions and apoptosis in PANC-1 and MiaPaCa-2 pancreatic cancer cells. Utilizing two-dimensional gel electrophoresis and mass spectrometry, we identify 13 essential proteins with significantly altered expressions in response to gemcitabine alone or combined with BDMC. Protein-protein interaction network analysis pinpoints glucose-regulated protein 78 (GRP78) as the key hub activated by BDMC. We then reveal that BDMC upregulates GRP78 and facilitates apoptosis through eIF2α/CHOP pathway. Moreover, DJ-1 and prohibitin, two identified markers of chemoresistance, are increased by gemcitabine in PANC-1 cells. This could be meaningfully reversed by BDMC, suggesting that BDMC partially offsets the chemoresistance induced by gemcitabine. In summary, these findings show that BDMC promotes apoptosis through a GRP78-dependent pathway and mitochondrial dysfunctions, and potentiates the antitumor effect of gemcitabine in human pancreatic cancer cells.

Topics: Adenocarcinoma; Antimetabolites, Antineoplastic; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Curcumin; Deoxycytidine; Diarylheptanoids; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Endoplasmic Reticulum Chaperone BiP; Eukaryotic Initiation Factor-2; Gemcitabine; Heat-Shock Proteins; Humans; Mitochondria; Pancreatic Neoplasms; Prohibitins; Protein Deglycase DJ-1; Protein Interaction Maps; Repressor Proteins; RNA Interference; Signal Transduction; Transcription Factor CHOP; Transfection

The incorporation of hydrophobic drugs into liposomes improve their bioavailability and leads to increased stability and anticancer activity, along with decreased drug toxicity. Curcumin (Cur) is a natural polyphenol compound with a potent anticancer activity in pancreatic adenocarcinoma (PA). In the present study, different types of Cur-loaded liposomal formulations were prepared and characterized in terms of size, shape, zeta potential, optimal drug-to-lipid ratio and stability at 4°C, 37°C; and in human plasma in vitro. The best formulation in terms of these parameters was PEGylated, cholesterol-free formulation based upon hydrogenated soya PC (HSPC:DSPE-PEG2000:Cur, termed H5), which had a 0.05/10 molar ratio of drug-to-lipid, was found to be stable and had a 96% Cur incorporation efficiency. All Cur-loaded liposomal formulations had potent anticancer activity on the PA cancer cell lines AsPC-1 and BxPC-3, and were less toxic to a normal cell line (NHDF). Furthermore, apoptosis-induction induced by Cur in PA cells was associated with morphological changes including cell shrinkage, cytoplasmic blebbing, irregularity in shape and the externalization of cell membrane phosphatidylserine, which was preceded by an increase in intracellular reactive oxygen species (ROS) generation and caspase 3/7 activation. Because the liposomal formulations tested here, especially the H5 variant which exhibited slow release of the Cur in the human plasma test, the formulation may be stable enough to facilitate the accumulation of pharmacologically active amounts of Cur in target cancer tissue by EPR. Therefore, our formulations could serve as a promising therapeutic approach for pancreatic cancer and other cancers.

Topics: Adenocarcinoma; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Curcumin; Humans; Liposomes; Pancreas; Pancreatic Neoplasms; Phosphatidylethanolamines; Polyethylene Glycols; Reactive Oxygen Species

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

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

Curcumin (1) down-regulates the expression as well as phosphorylation of epidermal growth factor receptor (EGFR) in lung adenocarcinoma cells expressing gefitinib-resistant EGFR. Thirty-seven newly synthesized curcumin analogues including dimethoxycurcumin (2, DMC) were evaluated for their effects on EGFR expression as well as phosphorylation in two gefitinib-resistant lung adenocarcinoma cell lines, CL1-5 (EGFR(wt)) and H1975 (EGFR(L858R+T790M)). Based on the identified structure-activity relationships, methoxy substitution at C-3', C-4', or both positions favored inhibitory activity (compounds 1, 2, 5, 8-15, 17, 36), while compounds with more polar substituents were generally less active in both cell lines. Compound 36 with a fluorine substituent at C-6' and its protonated counterpart 2 did not lose activity, suggesting halogen tolerance. In addition, a conjugated linker was essential for activity. Among all evaluated curcumin derivatives, compound 2 showed the best inhibitory effects on both wild-type and mutant EGFR by efficiently inducing gefitinib-insensitive EGFR degradation. Compound 23 also reduced gefitinib-induced gastrointestinal damage in the non-transformed intestinal epithelial cell line IEC-18.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Cell Line, Tumor; Curcumin; Drug Resistance, Neoplasm; ErbB Receptors; Gastrointestinal Diseases; Humans; Lung Neoplasms; Protein Kinase Inhibitors; Xenograft Model Antitumor Assays

Curcumin has been found to exhibit anticancer activity and certain studies have shown that curcumin triggers the apoptosis of human A549 lung adenocarcinoma cells. However, the mechanism underlying curcumin‑mediated apoptosis is not completely understood. The present study was designed to investigate the effect of curcumin on the induction of apoptosis and apoptosis‑related factors in human A549 lung adenocarcinoma cells. Treatment of A549 cells with curcumin caused a concentration‑dependent inhibition of cell growth and an increase in apoptosis, as confirmed by THE MTT assay, flow cytometry and morphology analysis. Curcumin‑treatment of A549 cells induced a loss of the mitochondrial membrane potential and increased cytosolic cytochrome c. Furthermore, curcumin‑induced apoptosis was accompanied by changes in intracellular oxidative stress‑related enzymes, including decreased intracellular reactive oxygen species levels, increased superoxide dismutase and decreased malondialdehyde and 4‑hydroxynonenal. In addition, induction of apoptosis was also accompanied by phosphorylation and activation of mitogen‑activated protein kinase signaling pathway factors c‑Jun N‑terminal kinase, p38 and extracellular signal-regulated kinase.

Topics: Adenocarcinoma; Apoptosis; Cell Line, Tumor; Curcumin; Humans; Lung Neoplasms; MAP Kinase Signaling System; Oxidative Stress

Curcumin is a nontoxic, chemopreventive agent possessing multifaceted functions. Our previous study showed that curcumin inhibits androgen receptor (AR) through modulation of Wnt/β-catenin signaling in LNCaP cells. Therefore, we investigated the in vivo effects of curcumin by using LNCaP xenografts.. LNCaP cells were subcutaneously inoculated in Balb/c nude mice. When the tumor volume reached greater than 100 mm(3), either curcumin (500 mg/kg body weight) or vehicle was administered through oral gavage three times weekly for 4 weeks. The expression of AR and intermediate products of Wnt/β-catenin were assessed.. Curcumin had an inhibitory effect on tumor growth during the early period, which was followed by a slow increase in growth over time. Tumor growth was delayed about 27% in the curcumin group. The mean prostate-specific antigen (PSA) doubling time in the curcumin group was approximately twice that in the untreated group. Curcumin significantly decreased AR expression at both the mRNA and protein level. The PSA levels tended to be reduced in the curcumin group. However, there were no significant changes in expression of Wnt/β-catenin pathway intermediates.. This study revealed that curcumin initially interferes with prostate cancer growth by inhibiting AR activity and possibly by reducing PSA expression. Further research is needed to investigate the plausible mechanism of the antiandrogenic action of curcumin.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; beta Catenin; Curcumin; Cyclin D1; Heterografts; Humans; Male; Mice, Inbred BALB C; Prostate-Specific Antigen; Prostatic Neoplasms; Receptors, Androgen; RNA, Messenger; Wnt Signaling Pathway

β-elemene, the active component of elemene (1-methyl-1-vinyl-2,4-diisopropenyl-cyclohexane), is a naturally occurring compound isolated from the traditional Chinese medicinal herb Curcuma wenyujin. Studies have confirmed that β-elemene enhances the radiosensitivity of lung cancer cell lines such as A549, by multiple pathways; however, their underlying mechanisms and pathways are yet to be elucidated. In the present study, two-dimensional differential in-gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometry were used to profile the different proteins in A549 cell xenograft models of both treatment groups. The protein/mRNA expression was assessed by reverse transcription-polymerase chain reaction and western blotting techniques in tumor samples from all treatment groups. As a critical player in redox regulation of cancer cells, inhibition of peroxiredoxin-1 (Prx-1) may be an effective option for enhancing the tumor response to radiation. We further verified Prx-1 expression at the transcription and translation levels. β-elemene at a dose of 45 mg/kg had little effect on the Prx-1 protein expression, which was correlated with a moderate antitumor effect. However, a 45 mg/kg dose of β-elemene significantly inhibited the Prx-1 mRNA expression, thereby suggesting a possible influence on the transcriptional process, and radiation significantly increased the Prx-1 mRNA/protein expression compared to the control group (p<0.01). Notably, Prx-1 mRNA/protein expression was significantly lower in the β-elemene/radiation co-treatment group compared to the baseline levels in the control group (p<0.01). These results suggest that radiation-induced Prx-1 expression is directly or indirectly suppressed by β-elemene, thus suggesting a new pathway by which to reverse radioresistance.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Animals; Cell Line, Tumor; Curcuma; Down-Regulation; Female; Humans; Lung Neoplasms; Medicine, Chinese Traditional; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Peroxiredoxins; Plant Extracts; Radiation Tolerance; Radiation-Sensitizing Agents; Radiography; RNA, Messenger; Sesquiterpenes; Tandem Mass Spectrometry; Transcription, Genetic; Transplantation, Heterologous

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

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

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

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

Curcumin, a polyphenol compound derived from the rhizome of the plant Curcuma longa L. has been verified as an anticancer compound against several types of cancer. However, understanding of the molecular mechanisms by which it induces apoptosis is limited. In this study, the anticancer efficacy of curcumin was investigated in human gastric adenocarcinoma SGC-7901 cells. The results demonstrated that curcumin induced morphological changes and decreased cell viability. Apoptosis triggered by curcumin was visualized using Annexin V-FITC/7- AAD staining. Curcumin-induced apoptosis of SGC-7901 cells was associated with the dissipation of mitochondrial membrane potential (MMP) and the release of cytochrome c into the cytosol. Furthermore, the down-regulation of Bcl-2 and up-regulation of Bax that led to the cleavage of caspase-3 and increased cleaved PARP was observed in SGC-7901 cells treated with curcumin. Therefore, curcumin-induced apoptosis of SGC-7901 cells might be mediated through the mitochondria pathway, which gives the rationale for in vivo studies on the utilization of curcumin as a potential cancer therapeutic compound.

Topics: Adenocarcinoma; Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; Caspase 3; Cell Line, Tumor; Cell Proliferation; Curcuma; Curcumin; Cytochromes c; Down-Regulation; Humans; Membrane Potential, Mitochondrial; Mitochondria; Mitochondrial Membranes; Permeability; Plant Preparations; Poly(ADP-ribose) Polymerases; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Stomach Neoplasms; Up-Regulation

Radix Curcumae is a traditional Chinese medicine that possesses antitumor properties, from which a new compound, diterpenoid C, was previously isolated and characterized.. In this study, using human colon adenocarcinoma SW620 cells, we further investigated the antitumor effects of diterpenoid C and the underlying mechanisms.. Cell proliferation was assessed with the MTT assay. Cell apoptosis and cell-cycle progression were analyzed with flow cytometry. The expression of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (p38 MAPK), and their phosphorylated forms, as well as caspase-3 protein levels were examined with Western blots.. Diterpenoid C could inhibit the proliferation of SW620 cells in a dose- and time-dependent manner. The median inhibitory concentration (IC50) at 24, 48, and 72 h were 28.31, 15.58, and 6.14 μg/ml, respectively. The inhibition of proliferation was found to be statistically significant as compared with the well-established drugs 5-fluorouracil (5-Fu) and oxaliplatin (L-OHP) (p < 0.01). Diterpenoid C also induced apoptosis and arrested cell cycle. It showed the highest apoptosis rate (98.20 ± 0.91%) at 70 μg/ml, at 72 h. Meanwhile, diterpenoid C suppressed the phosphorylation of ERK, JNK, and p38 MAPK proteins, and markedly induced the cleavage of caspase 3.. Diterpenoid C inhibits proliferation and induces apoptosis of cancer cells by suppressing the MAPK signaling pathway and inducing apoptotic factor caspase-3. Our results suggest that this novel compound might become a potent chemotherapeutic agent for the treatment of colon cancer and further studies are warranted.

Topics: Adenocarcinoma; Antineoplastic Agents, Phytogenic; Apoptosis; Caspase 3; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Curcuma; Diterpenes; Fluorouracil; Humans; Inhibitory Concentration 50; MAP Kinase Signaling System; Organoplatinum Compounds; Oxaliplatin; Time Factors

Sa-Tri-Lhung-Klod is a Thai traditional medicine remedy for postpartum in the lists of The National Drug List ofHerbal Medicine Products AD. It consists ofseventeen herbs and were obtained by maceration and used in the form of liquor for women's health care such as treatment ofamenorrhea, menopause and blood tonic. In addition, it also usedfor postpartum care for being anti-inflammation in postpartum and prevention of cancer in women.. To investigate cytotoxic activity ofSa-Tri-Lhung-Klod remedy extracts and its herbal ingredients against human ovarian carcinoma cell line (SKOV-3) and cervical adenocarcinoma (HeLa) cell line.. Sa-Tri-Lhung-Klod remedy and its plant ingredients were extracted by maceration in 95% ethanol and dried using evaporator. All extracts were testedfor cytotoxic activity by sulforhodamine B (SRB) assay.. Ethanolic extract ofSa-Tri-Lhung-Klod remedy displayed cytotoxic activity against SKOV-3 and HeLa with IC50 values of 72.84±1.07 and 47.24±2.83 μg/ml, respectively. It was classified as "less-active" according to the NCI guideline. However, Caesalpinia sappan, Mammea siamensis and Curcuma comosa showed high cytotoxic activity against SKOV-3 with IC50 values of 9.55±1.38 13.45±0.82 and 14.21±1.30 μg/ml, respectively. The ethanolic extracts ofCaesalpiniasappan and Mammea siamensis also exhibited cytotoxic activity against HeLa with IC50 values of 6.30±0.06 and 7.72±0.11 μg/ml, respectively.. These results support the use of Sa-Tri-Lhung-Klod remedy in Thai traditional medicine for preventing of ovarian cancer and cervical cancer Caesalpinia sappan, Curcuma comosa and Mammea siamensis were strikingly active against ovarian and cervical cancer cells. Their extracts have the potential for developing as new anti-cancer drugs for women health.

Topics: Adenocarcinoma; Caesalpinia; Cell Line, Tumor; Cell Survival; Curcuma; Drug Screening Assays, Antitumor; Female; HeLa Cells; Humans; In Vitro Techniques; Mammea; Medicine, Traditional; Ovarian Neoplasms; Plant Extracts; Plants, Medicinal; Uterine Cervical Neoplasms

Curcumin has potent antitumor activity against many types of human cancers. However, the inhibitory effects and possible mechanisms of curcumin on gallbladder cancer remains to be determined.. Using HAG-1 human gallbladder adenocarcinoma cells, we investigated the effects of curcumin on cell proliferation, apoptosis, cell-cycle perturbation, and signal proteins for survival, proliferation, and apoptosis.. Curcumin exhibited dose-dependent antitumor activity against HAG-1 cells, arresting the cells in G2/M phase, with progressive expansion of the apoptotic cell population. Upon curcumin treatment, AKT activation was substantially suppressed, with subsequent reduction of activities of mammalian target of rapamycin (mTOR) and its downstream molecules S6 kinase-1 (S6K1) and elF4E-binding protein-1 (4E-BP1), but constitutive activity of extracellular signal-regulated kinase (ERK1/2) was clearly enhanced. Curcumin reduced the expression and phosphorylation of anti-apoptotic Bcl-2, but did not affect the expressions of pro-apoptotic Bax and anti-apoptotic nuclear factor (NF-κB).. These results suggest that curcumin induces G2/M arrest and apoptosis through multiple mechanisms involving enhanced mitogen-activated protein (MAP) kinase activity, reduced AKT-mTOR activity, and reduced Bcl-2 function. These data provide a mechanistic rationale for the potential use of curcumin in the treatment of gallbladder cancer.

Topics: Adenocarcinoma; Antineoplastic Agents; Apoptosis; Blotting, Western; Cell Cycle; Cell Proliferation; Curcumin; Gallbladder Neoplasms; Humans; Immunoprecipitation; Tumor Cells, Cultured

Although curcumin has been studied as a potential anticancer drug targeting multiple signaling molecules, the role of oncogenic Src and Ras in curcumin sensitivity remains unknown. Using HAG-1 human adenocarcinoma cells transfected with either activated Src or Ras, we investigated here the functional role of these oncogenes in curcumin sensitivity. Activation of either Src or Ras did not confer resistance to curcumin, compared to vehicle-transfected cells. Curcumin enhanced Erk1/2 predominantly in Ras-activated cells, but inhibited Akt and its downstream molecules (mTOR and S6K1) regardless of these oncogene activations. The sub-G0/G1 apoptotic populations were substantially increased with demonstrable cleavage of PARP, but this increase was most prominent in Src-activated cells. Suppression of Bcl-xL level and enhanced expression of Bax were demonstrated in Src-activated, but not Ras-activated cells. By contrast, drastic increases of G2/M cell populations were seen in Ras-activated cells rather than Src-activated cells, suggesting a potential role of Ras/Erk1/2 activation in curcumin-induced G2/M arrest. These data indicate that curcumin-induced growth inhibition would be mediated mainly by G2/M arrest in Ras-driven cells but by apoptosis induction in Src-driven cells, providing a mechanistic rationale for the potential use of curcumin in the treatment of human cancers with activated Src or Ras.

Topics: Adenocarcinoma; Antineoplastic Agents; Apoptosis; bcl-X Protein; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; Dose-Response Relationship, Drug; Enzyme Activation; Flow Cytometry; G2 Phase Cell Cycle Checkpoints; Humans; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Poly(ADP-ribose) Polymerases; Proto-Oncogene Proteins c-akt; ras Proteins; src-Family Kinases

The aim of this paper is to compare the cytotoxicity and cellular uptake efficiency of three kinds of poly(b-benzyl-L-amino) block-poly(ethylene glycol) nanoparticles (PXA-PEG-NPs) using Calu-3 cells, and select one as a nasal drug delivery vector for curcumin (Cur). Poly(gamma-benzyl-L-glutamate) block-poly(ethylene glycol) nanoparticles (PBLG-PEG-NPs), poly(gamma-benzyl-L-lysine) block-poly(ethyleneglycol) nanoparticles (PZLL-PEG-NPs) and poly(gamma-benzyl-L-aspartate) block-poly(ethylene glycol) nanoparticles (PBLA-PEG-NPs) were prepared by emulsion-solvent evaporation method. MTT assays were used to evaluate the cytotoxicity of PXA-PEG-NPs against Calu-3 cells. The cellular uptake of nanoparticles was visualized by an inverted fluorescence microscope and quantified by a flow cytometer. The results indicated that even at high concentration of 2 mg x mL(-1) the three nanoparticles had no cytotoxicity on Calu-3 cells. Compared to the curcumin solution, the three curcumin-loaded PXA-PEG-NPs showed significantly higher cellular uptake efficiency on Calu-3 cells (at equal concentration of curcumin with 5 microg x mL(-1) Cur solution), PBLG-PEG-NPs group was the highest. The cellular uptake increased with incubation time, and has positive correlation with nanoparticle concentration. In brief, PXA-PEG-NPs are conducive to delivery Cur into cells, and PBLG-PEG-NPs might be provided as a good nasal drug delivery carrier.

Topics: Adenocarcinoma; Administration, Intranasal; Anti-Inflammatory Agents, Non-Steroidal; Aspartic Acid; Cell Line, Tumor; Cell Survival; Curcumin; Drug Carriers; Ethylene Glycol; Humans; Lung Neoplasms; Lysine; Nanoparticles; Particle Size; Polyethylene Glycols; Polyglutamic Acid

Curcumin is a major yellow pigment and active component of turmeric widely used as dietary spice and herbal medicine. This compound has been reported to be a promising antitumor agent, although the underlying molecular mechanisms are not fully understood yet. In this study, we reported that curcumin inhibited growth of lung adenocarcinoma cells, but had no cytotoxic activity to IMR-90 normal lung fibroblast cells. Curcumin induced autophagy in the A549 human lung adenocarcinoma cell line, evidenced by LC3 immunofluorescence analysis and immunoblotting assays on LC3 and SQSTM1. Moreover, the autophagy inhibitor 3-MA partly blocked the inhibitory effect of curcumin on the growth of A549 cells. Curcumin markedly increased the phosphorylation of AMP-activated protein kinase (AMPK) and acetylCoA carboxylase in A549 cells. At last, pharmacological blockade of the AMPK signaling pathway by compound C and genetic disruption of the AMPK signaling pathway with siRNA-mediated AMPKα1 knockdown impaired the autophagy-inducing effect of curcumin. Collectively, our data suggests that curcumin induces autophagy via activating the AMPK signaling pathway and the autophagy is important for the inhibiting effect of curcumin in lung adenocarcinoma cells.

Topics: Acetyl-CoA Carboxylase; Adenocarcinoma; AMP-Activated Protein Kinases; Antineoplastic Agents, Phytogenic; Autophagy; Cell Line, Tumor; Curcumin; Gene Knockdown Techniques; Humans; Lung Neoplasms; Phosphorylation; RNA, Small Interfering; Signal Transduction

Curcumin has shown promising therapeutic utilities for many diseases, including cancer; however, its clinical application is severely limited because of its poor stability under physiological conditions. Here we find that curcumin also loses its activity instantaneously in a reducing environment. Curcumin can exist in solution as a tautomeric mixture of keto and enol forms, and the enol form was found to be responsible for the rapid degradation of the compound. To increase the stability of curcumin, several analogues were synthesized in which the diketone moiety of curcumin was replaced by isoxazole (compound 2) and pyrazole (compound 3) groups. Isoxazole and pyrazole curcumins were found to be extremely stable at physiological pH, in addition to reducing atmosphere, and they can kill cancer cells under serum-depleted condition. Using molecular modeling, we found that both compounds 2 and 3 could dock to the same site of tubulin as the parent molecule, curcumin. Interestingly, compounds 2 and 3 also show better free radical scavenging activity than curcumin. Altogether, these results strongly suggest that compounds 2 and 3 could be good replacements for curcumin in future drug development.

Topics: Adenocarcinoma; Antineoplastic Agents; Apoptosis; Cell Proliferation; Curcumin; Flow Cytometry; Free Radical Scavengers; Humans; Isoxazoles; Ketones; Lung Neoplasms; Models, Chemical; Molecular Conformation; Molecular Structure; Pyrazoles; Structure-Activity Relationship; Tubulin; Tumor Cells, Cultured

Pancreatic cancer is a deadly disease killing 37,000 Americans each year. Despite two decades of research on treatment options, the chances of survival are still less than 5% upon diagnosis. Recently, chemopreventive strategies have gained considerable attention as an alternative to treatment. We have previously shown significant in vitro chemopreventive effects with low-dose combinations of aspirin, curcumin, and sulforaphane (ACS) on pancreatic cancer cell lines. Here, we report the results of 24-week chemopreventive study with the oral administration of ACS combinations on the N-nitrosobis (2-oxopropyl) amine (BOP)-treated Syrian golden hamster model to suppress the progression of pancreatic intraepithelial neoplasms (PanIN) using unmodified (free drug) combinations of ACS, and nanoencapsulated (solid lipid nanoparticles; SLN) combinations of aspirin, curcumin, and free sulforaphane. The use of three different doses (low, medium, and high) of unmodified ACS combinations exhibited reduction in tumor incidence by 18%, 50%, and 68.7% respectively; whereas the modified nanoencapsulated ACS regimens reduced tumor incidence by 33%, 67%, and 75%, respectively, at 10 times lower dose compared with the free drug combinations. Similarly, although the unmodified free ACS showed a notable reduction in cell proliferation, the SLN encapsulated ACS regimens showed significant reduction in cell proliferation at 6.3%, 58.6%, and 72.8% as evidenced by proliferating cell nuclear antigen expression. Cell apoptotic indices were also upregulated by 1.5, 2.8, and 3.2 times, respectively, compared with BOP control. These studies provide a proof-of-concept for the use of an oral, low-dose, nanotechnology-based combinatorial regimen for the long-term chemoprevention of pancreatic cancer.

Topics: Adenocarcinoma; Administration, Oral; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Aspirin; Carcinogens; Cell Line, Tumor; Cricetinae; Curcumin; Disease Models, Animal; Disease Progression; Drug Delivery Systems; Immunohistochemistry; In Situ Nick-End Labeling; Isothiocyanates; Lipids; Male; Mesocricetus; Nanoparticles; Nitrosamines; Pancreatic Neoplasms; Proliferating Cell Nuclear Antigen; Sulfoxides

Multi-drug resistance (MDR) is an essential aspect of human lung cancer chemotherapy failure. Recent studies have shown that vinorelbine is involved in underlying processes in human tumors, reversing the MDR inseveral types of cancer cells. However, the roles and potential mechanism are not fully clear. In this study, we explored effects of vinorelbine in multi-drug resistance reversal of human lung cancer A549/DDP cells. We found that vinorelbine increased drug sensitivity to cisplatin and intracellular accumulation of rhodamine-123, while decreasing expression of P-glycoprotein (P-gp), multi-drug resistance-associated protein (MRP1) and glutathione-S-transferase Π (GST-Π) in A549/DDP cells. At the same time, we also established downregulation of p-Akt and decreased transcriptional activation of NF-κB and twist after vinorelbine treatment. The results indicated that vinorelbine might be used as a potential therapeutic strategy in human lung cancer.

Topics: Adenocarcinoma; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; ATP Binding Cassette Transporter, Subfamily B, Member 1; Blotting, Western; Cell Proliferation; Curcumin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Glutathione; Glutathione S-Transferase pi; Humans; Lung Neoplasms; NF-kappa B; Phosphorylation; Proto-Oncogene Proteins c-akt; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Cells, Cultured; Vinblastine; Vinorelbine

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

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

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

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

The supermolecular curcumin (SMCCM) exhibiting remarkably improved solubility and release characteristics was fabricated to increase the oral bioavailability in rat as well as the antiproliferative and proapoptotic activities of curcumin (CCM) against human lung adenocarcinoma cell A549. SMCCM was characterized by differential scanning calorimetry, Fourier transform infrared spectroscopy, morphology and structure, aqueous solubility, and release behavior in vitro. Computer modeling of the supermolecular structure was performed. The pharmacokinetics, antiproliferative and proapoptotic activities of SMCCM were evaluated. The mechanisms by which SMCCM inhibited proliferation and induced apoptosis were identified. The formation of SMCCM was testified and the supermolecular structure was studied by a computer modeling technique. Compared to free CCM, SMCCM with much higher aqueous solubility exhibited obviously enhanced release and more favorable pharmacokinetic profiles, and, furthermore, SMCCM showed higher anticancer efficacy, enhanced induction of G2/M-phase arrest and apoptosis in A549 cells, which might be involved with the increases in reactive oxygen species production and intracellular Ca(2+) accumulation, and a decrease in mitochondrial membrane potential. SMCCM remarkably enhanced not only the oral bioavailability but also the antiproliferative and proapoptotic activities of CCM along with improved solubility and release characteristics of CCM.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Animals; Antineoplastic Agents; Apoptosis; Calcium; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Curcumin; Humans; Lung; Lung Neoplasms; Male; Models, Molecular; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Solubility

The modifying effects of 4-methylthio-3-butenyl isothiocyanate (MTBITC) and curcumin were investigated in N-nitrosobis(2-oxopropyl)amine (BOP)-initiated hamsters. Male 6-week-old Syrian hamsters were subcutaneously injected with 10 mg/kg body weight (b.w.) of BOP four times a week, and fed a diet supplemented with 80 mg/kg diet of MTBITC, equivalent to 4.6 mg/kg b.w./day for the initiation stage or 3.8 mg/kg b.w./day for the postinitiation stage administration, respectively, or 2000 mg/kg diet of curcumin, equivalent to 118.8 mg/kg b.w./day for the initiation stage or 100.8 mg/kg b.w./day for the postinitiation stage administration, respectively. The incidence of combined pancreatic lesions, including atypical hyperplasias and adenocarcinomas, was significantly decreased to 55% (P < 0.05) by the 80 mg/kg diet MTBITC given during the initiation stage as compared to the BOP alone group (85%) but not by the curcumin administration at 16 weeks after the BOP-treatment. In the second study, the multiplicity of combined pancreatic lesions was also significantly decreased to 0.50 ± 0.51 (P < 0.05) by 700 mg/kg diet MTBITC given in the initiation stage (equivalent to 59.0 mg/kg b.w./day) as compared to the BOP alone group (1.10 ± 1.02). Our results indicate that the naturally occurring isothiocyanate MTBITC may exert preventive effects against BOP-initiation of hamster pancreatic carcinogenesis.

Topics: Adenocarcinoma; Animals; Anticarcinogenic Agents; Carcinogens; Cricetinae; Curcumin; Diet; Hyperplasia; Isothiocyanates; Male; Mesocricetus; Nitrosamines; Pancreas; Pancreatic Neoplasms

The purpose of this manuscript was to study the regulation effects of β-elemene combined with radiotherapy on three different gene expressions in lung adenocarcinoma A549 cell. mTOR gene, HIF-1α gene, Survivin gene were included in the gene group. Cell culture and RT-PCR were applied to finish this research. Hypoxia Control group, Hypoxia β-elemene group, Hypoxia β-elemene combined with irradiation group were set to compare the differences of three different gene expressions. The most active effects were found in the group of Hypoxia irradiation combined with β-elemene. In this group, the mTOR gene, HIF-1α gene, Survivin gene expressions were all down-regulated when compared with the single treatment groups, and there were significantly statistical differences.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Chemotherapy, Adjuvant; Curcuma; Down-Regulation; Gene Expression; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Inhibitor of Apoptosis Proteins; Lung Neoplasms; Phytotherapy; Plant Extracts; Reverse Transcriptase Polymerase Chain Reaction; Sesquiterpenes; Survivin; TOR Serine-Threonine Kinases

The present study demonstrates that curcumin acts as pro-oxidant and sensitizes human lung adenocarcinoma epithelial cells (A549) to apoptosis via intracellular redox status mediated pathway. Results indicated that curcumin induced cell toxicity (light microscopy and MTT assay) and apoptosis (AnnexinV-FITC/PI labeling and caspase-3 activity) in these cells. These events seem to be mediated through generation of reactive oxygen species (ROS) and superoxide radicals (SOR) and enhanced levels of lipid peroxidation. These changes were accompanied by increase in oxidized glutathione (GSSG), reduced glutathione (GSH) and gamma-glutamylcysteine synthetase (gamma-GCS) activity, but decrease in GSH/GSSG ratio. The induction of apoptosis and decrease in GSH/GSSG ratio was also accompanied by sustained phosphorylation and activation of p38 mitogen activated protein kinase (MAPK). On the other hand, addition of N-acetyl cysteine (NAC), an antioxidant, blocked the curcumin-induced ROS production and rescued malignant cells from curcumin-induced apoptosis through caspase-3 deactivation. However, L-buthionine sulfoximine (BSO), a GSH synthesis blocking agent, further enhanced curcumin-induced ROS production and apoptosis in A549 cells. Decreased GSH/GSSG ratio seems to be a crucial factor for the activation of MAPK signaling cascade by curcumin. The study therefore, provides an insight into the molecular mechanism involved in sensitization of lung adenocarcinoma cells to apoptosis by curcumin.

Topics: Acetylcysteine; Adenocarcinoma; Antineoplastic Agents, Phytogenic; Antioxidants; Apoptosis; Buthionine Sulfoximine; Caspase 3; Cell Line, Tumor; Curcumin; Drug Screening Assays, Antitumor; Enzyme Activation; Enzyme Induction; Glutamate-Cysteine Ligase; Glutathione; Humans; Lipid Peroxidation; Lung Neoplasms; MAP Kinase Signaling System; Oxidants; Oxidation-Reduction; Phosphorylation; Protein Processing, Post-Translational; Reactive Oxygen Species; RNA, Messenger; RNA, Neoplasm; Superoxides

CLEFMA or 4-[3,5-bis(2-chlorobenzylidene-4-oxo-piperidine-1-yl)-4-oxo-2-butenoic acid] is a curcuminoid being developed as an anticancer drug. We recently reported that it potently inhibits proliferation of various cancer cells. In this project, we investigated the effect of CLEFMA on gene expression profile in H441 lung adenocarcinoma cells, and studied its mechanism of action. In microarray data, we observed a deregulation of genes involved in redox and glutamate metabolism. Based on the affected ontologies, we hypothesized that antiproliferative activity of CLEFMA could be a result of the induction of reactive oxygen species (ROS). We tested this hypothesis by determining the levels of glutathione (GSH) and ROS in H441 cells treated with CLEFMA. We observed a rapid depletion of intracellular GSH/GSSG ratio. Using a cell-permeable fluorogenic substrate, we found that CLEFMA significantly induced ROS in a time- and dose-dependent manner (p < 0.05). Flow-cytometry with a mitochondria-selective fluorescent reporter of ROS indicated that the CLEFMA-induced ROS was of mitochondrial origin. In contrast to the cancer cells, the normal lung fibroblasts (CCL-151) did not show any increase in ROS and were resistant to CLEFMA-induced cell death. Furthermore, the addition of antioxidants, such as catalase, superoxide dismutase and N-acetylcysteine, rescued cancer cells from CLEFMA-induced cell death. Gene expression pathway analysis suggested that a transcription factor regulator Nrf2 is a pivotal molecule in the CLEFMA-induced deregulation of redox pathways. The immunoblotting of Nrf2 showed that CLEFMA treatment resulted in phosphorylation and nuclear translocation of Nrf2 in a time-dependent fashion. Based on these results, we conclude that induction of ROS is critical for the antiproliferative activity of CLEFMA and the Nrf2-mediated oxidative stress response fails to salvage H441 cells.

Topics: Active Transport, Cell Nucleus; Adenocarcinoma; Adenocarcinoma of Lung; Antineoplastic Agents, Phytogenic; Antioxidants; Benzylidene Compounds; Blotting, Western; Cell Death; Cell Line, Tumor; Cell Proliferation; Curcumin; Dose-Response Relationship, Drug; Flow Cytometry; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Glutathione; Humans; Lung Neoplasms; NF-E2-Related Factor 2; Oligonucleotide Array Sequence Analysis; Oxidation-Reduction; Oxidative Stress; Phosphorylation; Piperidones; Reactive Oxygen Species; Time Factors

The rhizome of Curcuma longa (turmeric) is often used in Asia as a spice and as a medicine. Its most well-studied component, curcumin, has been shown to exhibit poor bioavailability in animal studies and clinical trials. We hypothesized that the presence of lipophilic components (e.g., turmerones) in turmeric extract would affect the absorption of curcumin. The effects of turmerones on curcumin transport were evaluated in human intestinal epithelial Caco-2 cells. The roles of turmerones on P-glycoprotein (P-gp) activities and mRNA expression were also evaluated. Results showed that in the presence of α- and aromatic turmerones, the amount of curcumin transported into the Caco-2 cells in 2 hours was significantly increased. α-Turmerone and verapamil (a P-gp inhibitor) significantly inhibited the efflux of rhodamine-123 and digoxin (i.e., inhibited the activity of P-gp). It is interesting that aromatic turmerone significantly increased the rhodamine-123 efflux and P-gp (MDR1 gene) mRNA expression levels. The effects of α- and aromatic turmerones on curcumin transport as well as P-gp activities were shown here for the first time. The presence of turmerones did affect the absorption of curcumin in vitro. These findings suggest the potential use of turmeric extract (including curcumin and turmerones), rather than curcumin alone, for treating diseases.

Topics: Adenocarcinoma; Antineoplastic Agents, Phytogenic; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Caco-2 Cells; Cell Survival; Colonic Neoplasms; Curcuma; Curcumin; Enterocytes; Gastrointestinal Agents; Gene Expression Regulation; Humans; Intestinal Absorption; Ketones; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Neoplasm Proteins; Phytotherapy; Plant Extracts; RNA, Messenger; Sesquiterpenes; Solubility

Curcumin, a yellow pigment derived from Curcuma longa Linn, has been favored by the Eastern as dietary ingredients for centuries. During the past decade, extensive investigations have revealed curcumin sensitized various chemotherapeutic agents in human breast, colon, pancreas, gastric, liver, brain and hematological malignant disorders in vivo and in vitro. Several pathways and specific targets including NF-κB, STAT3, COX-2, Akt and multidrug resistant protein have been identified to facilitate curcumin as a chemosensitizer. Recent studies suggest HIF-1α participated in the development of drug resistance in cancer cells and targeting HIF-1α either by RNAi or siRNA successfully overcame chemotherapeutic resistance. To investigate the mechanism basis of curcumin as a chemosensitizer in lung cancer, we examined curcumin's effects on HIF-1α in cis-platin (DDP) sensitive A549 and resistant A549/DDP cell lines by RT-PCR and Western blot. HIF-1α in A549/DDP cells was found to be overexpressed at both mRNA and protein levels together with a poor response to DDP. Results from transient transfection and flow cytometry showed the HIF-1α abnormality contributed to DDP resistance in A549/DDP lung cancer cells. Combined curcumin and DDP treatment markedly inhibited A549/DDP cells proliferation, reversed DDP resistance and triggered apoptotic death by promoting HIF-1α degradation and activating caspase-3, respectively. Expression of HIF-1α-dependent P-gp also seemed to decrease as response to curcumin in a dose-dependent manner. Our findings shed light on drug resistant reversing effect of curcumin in lung cancer cells by inhibiting HIF-1α expression and activating caspase-3.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Apoptosis; ATP Binding Cassette Transporter, Subfamily B, Member 1; Caspase 3; Cell Line, Tumor; Cell Proliferation; Cisplatin; Curcumin; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Lung Neoplasms

Curcumin has been suggested to possess anti-neoplastic properties. As oesophageal adenocarcinoma (OA) and Barrett's oesophagus (BO) represent a neoplastic series, we postulated that curcumin supplementation may slow neoplastic progression at this site. Our aim was to investigate the effects of curcumin in vitro and in vivo on markers of oesophageal cancer progression.. We investigated the in vitro ability of curcumin to prevent bile acid-induced DNA damage using micronucleus assay and nuclear factor-kappaB (NF-κB) activity in the oesophageal cell lines (OE33) using real-time PCR of the extracted RNA. We also analysed NF-κB p65 activation in curcumin-pre-treated OE33 cells exposed to deoxycholic acid (DCA) using ELISA. In another pilot study, BO patients took a daily 500 mg curcumin tablet for 7 days prior to their endoscopy. In biopsies collected from these patients (n=33, 16 curcumin, 17 control), we examined NF-κB-driven gene expression (interleukin (IL)-8, inhibitor- kappaB (I-κB)) using real-time PCR of the extracted RNA from the biopsy sample. The apoptotic frequency was assessed by counting the number of apoptotic bodies in the epithelial cells from the Barrett's tissue with and without curcumin.. In vitro, curcumin (50 μM) significantly abrogated DNA damage and NF-κB activity induced by bile. Pretreating OE33 cells with curcumin (50 μM) completely abolished the ability of DCA (300 μM) to activate NF-κB. In vivo, IL-8 expression was non-significantly suppressed in the curcumin-supplemented patients compared to the squamous control tissue, whilst also showing a doubling in the apoptotic frequency compared to non-supplemented control patients.. Curcumin abrogated bile-driven effects in vitro. The in vivo data also suggests that curcumin supplementation had beneficial effects (increased apoptosis, potentially reduced NF-κB activity) in the Barrett's tissues themselves, despite poor delivery of the curcumin to the oesophagus.

Topics: Adenocarcinoma; Aged; Anticarcinogenic Agents; Antineoplastic Agents; Apoptosis; Barrett Esophagus; Bile; Biopsy; Cell Line, Tumor; Curcumin; DNA Damage; Enzyme-Linked Immunosorbent Assay; Esophageal Neoplasms; Female; Humans; Male; Middle Aged; NF-kappa B; Pilot Projects; Real-Time Polymerase Chain Reaction

Radiation pneumonitis (RP) is an important dose-limiting toxicity during thoracic radiotherapy. Previous investigations have shown that curcumin is used for the treatment of inflammatory conditions and cancer, suggesting that curcumin may prevent RP and sensitize cancer cells to irradiation. However, the clinical advancement of curcumin is limited by its poor water solubility and low bioavailability after oral administration. Here, a water-soluble liposomal curcumin system was developed to investigate its prevention and sensitizing effects by an intravenous administration manner in mice models. The results showed that liposomal curcumin inhibited nuclear factor-κB pathway and downregulated inflammatory factors including tumor necrosis factor-α, interleukin (IL)-6, IL-8, and transforming growth factor-β induced by thoracic irradiation. Furthermore, the combined treatment with liposomal curcumin and radiotherapy increased intratumoral apoptosis and microvessel responses to irradiation in vivo. The significantly enhanced inhibition of tumor growth also was observed in a murine lung carcinoma (LL/2) model. There were no obvious toxicities observed in mice. The current results indicate that liposomal curcumin can effectively mitigate RP, reduce the fibrosis of lung, and sensitize LL/2 cells to irradiation. This study also suggests that the systemic administration of liposomal curcumin is safe and deserves to be investigated for further clinical application.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Analysis of Variance; Animals; Carcinoma, Lewis Lung; Cell Line, Tumor; Combined Modality Therapy; Curcumin; Cytokines; Histocytochemistry; Liposomes; Lung Neoplasms; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic; Radiation Pneumonitis; Radiation-Sensitizing Agents; Radiography, Thoracic

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

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

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

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

Endoplasmic reticulum (ER) stress-induced cancer cell apoptosis has become a novel signaling target for development of cancer therapeutic drugs. Curcumin exhibits growth-suppressive activity against a variety of cancer cells. We previously synthesized a series of monocarbonyl analogues of curcumin with strong cytotoxicity against tumor cells. In this study, we found that only compound 19 [(1E,4E)-1,5-bis(2,3-dimethoxyphenyl)penta-1,4-dien-3-one] can induce C/EBP-homologous protein (CHOP) expression in human lung cancer H460 cells. Treatment with 19 induced H460 cell apoptosis in a dose-responsive manner, and this effect was associated with corresponding increases in a series of key components in ER stress-mediated apoptosis pathway, followed by caspase cleavage and activation. However, curcumin at the same concentrations does not display such properties. CHOP knockdown by specific siRNA attenuated 19-induced cell apoptosis, further indicating that the apoptotic pathway is ER stress-dependent. In vivo, 19 showed a dramatic 53.5% reduction in H460 xenograft tumor size after 22 days of treatment. Taken together, these mechanistic insights on the novel compound 19, with nontoxicity, may provide us with a novel anticancer candidate.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Animals; Antineoplastic Agents; Apoptosis; Caspases; Cell Line, Tumor; Cell Proliferation; Curcumin; Endoplasmic Reticulum; Female; Humans; Lentivirus; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Structure; Molecular Targeted Therapy; Oxidative Stress; RNA, Small Interfering; Signal Transduction; Transcription Factor CHOP; Xenograft Model Antitumor Assays

Curcumin, a phenol in turmeric (Curcuma longa), has been studied for the last decade as a potential anticancer drug. It has been shown to reduce viability of the highly malignant, metastatic rat mammary gland cell line ENU1564 in culture and reduce metastasis of these cells injected into nude mice. The purpose of this study was to identify the mechanisms by which curcumin induces apoptosis in these ENU1564 cells in vitro, and to examine its effects on mitochondrial membrane potential and mitochondrial Ca(2+) homeostasis. The results show that curcumin induced apoptosis in ENU1564 cells through the intrinsic pathway of apoptosis, as evident by an increase in mitochondrial Ca(2+) accumulation and a decrease in mitochondrial membrane potential. However, treatment of the ENU1564 cells with the mitochondrial uniporter inhibitor RU-360 prior to curcumin treatment partially inhibited the curcumin effects. SKF-96365, a store-operated Ca(2+) channel blocker, suppressed the curcumin effect on mitochondrial Ca(2+). In addition, curcumin down-regulated the expressions of Bcl-2 and procaspase-3 and increased the production of reactive oxygen species in ENU1564 cells. These data suggest that the mitochondrial Ca(2+) is the leading factor by which curcumin induced apoptosis in ENU1564 cells, followed by reactive oxygen species production and inhibition of Bcl-2 oncoprotein.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Apoptosis; Biological Transport; Calcium; Caspase 3; Cell Line, Tumor; Cell Survival; Curcumin; Female; Gene Expression Regulation, Neoplastic; Imidazoles; Mammary Neoplasms, Animal; Membrane Potential, Mitochondrial; Mitochondria; Proto-Oncogene Proteins c-bcl-2; Rats; Reactive Oxygen Species; Ruthenium Compounds; Signal Transduction

Non-small cell lung cancer (NSCLC) patients with L858R or exon 19 deletion mutations in epidermal growth factor receptor (EGFR) have good responses to the tyrosine kinase inhibitor (TKI), gefitinib. However, patients with wild-type EGFR and acquired mutation in EGFR T790M are resistant to gefitinib treatment. Here, we showed that curcumin can improve the efficiency of gefitinib in the resistant NSCLC cells both in vitro and in vivo models.. After screening 598 herbal and natural compounds, we found curcumin could inhibit cell proliferation in different gefitinib-resistant NSCLC cell lines; concentration-dependently down-regulate EGFR phosphorylation through promoting EGFR degradation in NSCLC cell lines with wild-type EGFR or T790M EGFR. In addition, the anti-tumor activity of gefitinib was potentiated via curcumin through blocking EGFR activation and inducing apoptosis in gefitinib-resistant NSCLC cell lines; also the combined treatment with curcumin and gefitinib exhibited significant inhibition in the CL1-5, A549 and H1975 xenografts tumor growth in SCID mice through reducing EGFR, c-MET, cyclin D1 expression, and inducing apoptosis activation through caspases-8, 9 and PARP. Interestingly, we observed that the combined treatment group represented better survival rate and less intestinal mucosal damage compare to gefitinib-alone therapy. We showed that curcumin attenuated the gefitinib-induced cell proliferation inhibition and apoptosis through altering p38 mitogen-activated protein kinase (MAPK) activation in intestinal epithelia cell.. Curcumin potentiates antitumor activity of gefitinib in cell lines and xenograft mice model of NSCLC through inhibition of proliferation, EGFR phosphorylation, and induction EGFR ubiquitination and apoptosis. In addition, curcumin attenuates gefitinib-induced gastrointestinal adverse effects via altering p38 activation. These findings provide a novel treatment strategy that curcumin as an adjuvant to increase the spectrum of the usage of gefitinib and overcome the gefitinib inefficiency in NSCLC patients.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blotting, Western; Carcinoma, Non-Small-Cell Lung; Cell Line; Cell Line, Tumor; Cell Proliferation; Curcumin; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Drug Synergism; Enzyme Activation; ErbB Receptors; Gefitinib; Humans; Intestinal Mucosa; Intestines; Lung Neoplasms; Mice; Mice, SCID; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Quinazolines; Ubiquitination; Xenograft Model Antitumor Assays

Curcumin, a polyphenolic compound, is the active component of Curcuma longa and has been extensively investigated as an anticancer drug that modulates multiple pathways. Eukaryotic initiation factors (eIFs) have been known to play important roles in translation initiation, which controls cell growth and proliferation. Little is known about the effects of curcumin on eIFs in lung cancer. The objective of this study was to exam the curcumin cytotoxic effect and modulation of two major rate-limiting translation initiation factors, including eIF2α and eIF4E protein expression levels in lung adenocarcinoma epithelial cell line A549. Cytotoxicity was measured by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and protein changes were determined by Western blot. A549 cells were treated with 0-240 μM curcumin for 4-96 h. The inhibitory effects of curcumin on cytotoxicity were dose- and time-dependent (P < 0.001). The 50% inhibitory curcumin concentrations (IC50s) at 24, 48, 72, and 96 h were 93, 65, 40, and 24 μM, respectively. Protein expressions of eIF2α, eIF4E, Phospho-4E-BP1 were down-regulated, while Phospho-eIF2α and Phospho-eIF4E were up-regulated after A549 cells were treated with 20 and 40 μM curcumin for 24 h. In addition, the effects of curcumin on these protein expression changes followed a significant dose-response (P < 0.05, trend test). These findings suggest that curcumin could reduce cell viability through prohibiting the initiation of protein synthesis by modulating eIF2α and eIF4E.

Topics: Adaptor Proteins, Signal Transducing; Adenocarcinoma; Cell Cycle Proteins; Cell Death; Cell Line, Tumor; Curcumin; Epithelial Cells; Eukaryotic Initiation Factor-2; Eukaryotic Initiation Factor-4E; Eukaryotic Initiation Factors; Humans; Lung Neoplasms; Phosphoproteins; Phosphorylation

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

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

Letrozole is an aromatase inhibitor that is used in the treatment of estrogen-sensitive tumors such as endometrial carcinoma, however, its therapeutic effect is still to be further improved. It is reported that curcumin has antitumor capability and can enhance the sensitivity of tumor cells to anticancer agents. This study was to investigate the inhibitory effect of letrozole combination with curcumin on the implanted endometrial tumor growth.. Nude mice were implanted with endometrial carcinoma RL-952 cells. All tumor-bearing mice were randomly divided into 5 groups: control(without treatment), Let(1) (letrozole, 1 microg/d), Let(10) (letrozole, 10 microg/d), Cur [ curcumin, 300 mg/kg.d)], and Let + Cur group [10microg/d letrozole + 50mg/ (kg.d) curcumin]. The tumor growth was monitored. Tumor cells apoptosis was detected in both control and treated groups. The expressions of bcl-2 mRNA and bcl-2 protein were detected using RT-PCR and Western blot, respectively.. Fifty mice were successfully implanted with the endometrial tumor. Treatment with letrozole markedly inhibited tumor growth; the inhibitory effect was further enhanced by the combination of letrozole and curcumin. The inhibitory rates in Let (1), Let (10), the Cur, and the Let + Cur groups were 15.95%, 22.49%, 21.57%, and 35.89%, respectively. Treatment with curcumin inhibited the expression of bcl-2 in tumor cells at the mRNA and protein levels. The apoptosis rates in the control group and the four experimental groups mentioned above were 16.97%, 32.90%, 35.80%, 34.16%, and 47.24%, respectively. Tumor cells apoptosis were observed in mice treated with either letrozole or curcumin; however, combination of letrozole and curcumin further enhanced the inhibitory rate in tumor growth.. Treatment with letrozole or curcumin could inhibit the xenografted endometrial tumor growth by inducing apoptosis in tumor cells. Combination of letrozole and curcumin further enhanced the inhibitory effect of tumor growth.

Topics: Adenocarcinoma; Animals; Apoptosis; Cell Cycle; Cell Line, Tumor; Curcumin; Drug Synergism; Endometrial Neoplasms; Female; Humans; Letrozole; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Nitriles; Proto-Oncogene Proteins c-bcl-2; Random Allocation; Receptors, Estrogen; RNA, Messenger; Triazoles; Tumor Burden; Xenograft Model Antitumor Assays

Several studies have shown that curcumin can induce apoptosis and inhibit growth in human A549 lung adenocarcinoma cells. However, the mechanism is not completely understood yet. The present study was designed to investigate the effects of curcumin on A549 cells to better understand its apoptosis and apoptosis-related factors in vitro. The apoptosis induction, intracellular reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were examined by confocal fluorescence microscope and flow cytometry. The MAPK protein expression was examined by Western blot analysis. After treatment with curcumin, apoptosis were observed. Curcumin-induced apoptosis was accompanied by an increase of intracellular ROS level and a loss of MMP. In addition, induction of apoptosis was also accompanied by sustained phosphorylation and activation of JNK, p38 and ERK. However, pretreatment with MAPK inhibitors had no effect upon curcumin-induced apoptosis. GSH and NAC, an anti-oxidant agent, blocked the curcumin-induced ROS production, MMP loss and rescued cells from curcumin-induced apoptosis. Our results indicated that curcumin induced apoptosis in A549 cells through a reactive oxygen species-dependent mitochondrial signaling pathway and independent of MAPK signaling pathway.

Topics: Adenocarcinoma; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Curcumin; Drug Evaluation, Preclinical; Humans; Lung Neoplasms; MAP Kinase Signaling System; Membrane Potential, Mitochondrial; Mitochondria; Reactive Oxygen Species; Signal Transduction

Curcumin is a natural compound that has been extensively observed due to its potential as an anticancer drug. Curcumin restrains cancer cell progression via telomerase activity suppression. However, the exact mechanism is still unknown. In this study, we demonstrate that the effects of curcumin on cell viability and telomerase activity can be blunted by reactive oxygen species (ROS) inhibitor N-acetyl cysteine (NAC). The ROS induced by curcumin in A549 cells was detected by flow cytometry. Using Western blot and RT-PCR, human telomerase reverse transcriptase (hTERT) decreased in the presence of curcumin. Sp1 is one of the important transcription factors in hTERT expression. Our data showed that curcumin decreases the expression of Sp1 through proteasome pathway. In addition, NAC blunted the Sp1 reduction and hTERT downregulation by curcumin. Further, reporter assay and DNA affinity precipitation assay confirmed the influence of curcumin on Sp1 in hTERT regulation. This is the first study to demonstrate that curcumin induces ROS production resulting in Sp1 binding activity inhibition and hTERT downregulation.

Topics: Acetylcysteine; Adenocarcinoma; Cell Line, Tumor; Cell Shape; Cell Survival; Curcumin; Down-Regulation; Humans; Lung Neoplasms; Reactive Oxygen Species; Sp1 Transcription Factor; Telomerase

Several studies have shown that curcumin can induce apoptosis and inhibit growth in human tumor cell lines. However, the mechanism is not completely understood yet. The present studies were designed to investigate the effects of curcumin on human A549 lung adenocarcinoma cells lines to better understand its effect on apoptosis and apoptosis-related genes in vitro. Apoptosis induction, mitochondria membrane potential, mitochondria structure, and apoptotic associated gene expression were examined by flow cytometric assay, confocal microscopy, Western blotting and electron microscopy. After treatment with curcumin, percentage of apoptotic cells increased dose- and time-dependently, and morphology observation revealed typical apoptotic features. Our data further indicated that the expression of Bax proteins in A549 cells was increased in a dose-dependent manner, whereas the expression of Bcl-2 was significantly decreased, thus the ratio of Bax/Bcl-2 was increased. The apoptotic process was accompanied by the change of mitochondrial function and structure which led to release of the cytochrome c, and activation of caspase-9 and caspase-3. Furthermore, curcumin also induced a dose-dependent cleavage of PARP. Caspases activation during the course of curcumin-induced apoptosis was additionally confirmed by using a broad-spectrum caspases inhibitor, Z-VAD-fmk. As expected, the inhibitor was able to decrease curcumin-induced apoptosis on A549 cells. These results suggested that mitochondria played an important role in the curcumin-induced apoptosis, and mitochondria membrane potential loss initiated apoptosis via the activation of caspases.

Topics: Adenocarcinoma; Amino Acid Chloromethyl Ketones; Antineoplastic Agents, Phytogenic; Apoptosis; bcl-2-Associated X Protein; Blotting, Western; Caspase 3; Caspase 9; Cell Line, Tumor; Cell Shape; Curcumin; Cysteine Proteinase Inhibitors; Cytochromes c; Dose-Response Relationship, Drug; Flow Cytometry; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Membrane Potential, Mitochondrial; Microscopy, Confocal; Microscopy, Electron, Transmission; Mitochondria; Poly(ADP-ribose) Polymerases; Proto-Oncogene Proteins c-bcl-2; Time Factors

Gemcitabine is a first line cancer drug widely used for the treatment of pancreatic cancer. However, its therapeutic efficiency is significantly limited by resistance of pancreatic cancer cells to this and other chemotherapeutic drugs. We have investigated the cytotoxic effect of Turmeric Force (TF), a supercritical and hydroethanolic extract of turmeric, alone and in combination with gemcitabine in two pancreatic carcinoma cell lines (BxPC3 and Panc-1). TF is highly cytotoxic to BxPC3 and Panc-1 cell lines with IC50 values of 1.0 and 1.22 microg/ml, respectively with superior cytotoxicity than curcumin. Gemcitabine IC50 value for both of these cell line is 0.03 microg/ml; however, 30-48% of the pancreatic cancer cells are resistant to gemcitabine even at concentrations >100 microg/ml. In comparison, TF induced cell death in 96% of the cells at 50 microg/ml. The combination of gemcitabine and TF was synergistic with IC90 levels achieved in both pancreatic cancer cell lines at lower concentrations. CalcuSyn analysis of cytotoxicity data showed that the Gemcitabine + Turmeric Force combination has strong synergism with combination index (CI) values of 0.050 and 0.183 in BxPC3 and Panc-1 lines, respectively at IC50 level. This synergistic effect is due to the increased inhibitory effect of the combination on nuclear factor-kappaB activity and signal transducer and activator of transcription factor 3 expression as compared to the single agent.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Proliferation; Curcumin; Cyclooxygenase 2; Deoxycytidine; Drug Synergism; Gemcitabine; Humans; Immunoblotting; Interleukin-8; NF-kappa B; Pancreatic Neoplasms; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; STAT3 Transcription Factor

Curcumin extracted from the rhizomes of Curcuma longa L. has been shown to have inhibitory effects on cancers through its anti-proliferative and pro-apoptotic activities. Emerging evidence demonstrates that curcumin can overcome drug resistance to classical chemotherapies. Thus, the mechanisms underlying the anti-tumor activities of curcumin require further study. In our study, we first demonstrated that curcumin had anti-cancer effects on A549/DDP multidrug-resistant human lung adenocarcinoma cells. Further studies showed that curcumin altered miRNA expression; in particular, significantly downregulated the expression of miR-186 * in A549/DDP. In addition, transfection of cells with a miR-186 * inhibitor promoted A549/DDP apoptosis, and overexpression of miR-186 * significantly inhibited curcumin-induced apoptosis in A549/DDP cells. These observations suggest that miR-186 * may serve as a potential gene therapy target for refractory lung cancer that is sensitive to curcumin.

Topics: Adenocarcinoma; Antineoplastic Agents; Apoptosis; Curcumin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; MicroRNAs; Signal Transduction

Recently, studies have investigated the significance of the Wnt/β-catenin pathway in prostate cancer. The transcriptional activity of the androgen receptor (AR) is modulated by interaction with coregulators, one of which is β-catenin. Curcumin, a dietary yellow pigment of Curcuma longa, has emerged as having a chemopreventive role. Although curcumin has been shown to inhibit AR expression, its molecular mechanism has not been fully elucidated. In this study, whether curcumin mediates the Wnt/β-catenin signaling pathway with regard to AR/β-catenin interactions was studied. Curcumin was shown to induce significant inhibition of AR expression in a dose-dependent manner. Marked curcumin-induced suppression of β-catenin was shown in the nuclear and cytoplasmic extracts as well as whole cell lysates. Further analysis revealed that phosphorylation of Akt and glycogen synthase kinase-3β were attenuated, but phosphorylated β-catenin was increased after curcumin treatment. Finally, cyclin D1 and c-myc, the target gene of the β-catenin/T-cell factor transcriptional complex, were also decreased. These findings suggest that curcumin modulates the Wnt/β-catenin signaling pathway and might have a significant role in mediating inhibitory effects on LNCaP prostate cancer cells.

Topics: Adenocarcinoma; Antineoplastic Agents; beta Catenin; Cell Line, Tumor; Cell Nucleus; Cell Proliferation; Curcumin; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Humans; Male; Prostatic Neoplasms; Protein Binding; Receptors, Androgen; Signal Transduction; Wnt1 Protein

The aim of this study was to evaluate the effect of curcumin (CUR) in oral bioavailability and therapeutic efficacy of paclitaxel (PTX) administered in nanoemulsion to SKOV3 tumor-bearing nu/nu mice. Oral administration of the mice with CUR at 50 mg/kg for 3 consecutive days resulted in a down regulation of intestinal P-glycoprotein (Pgp) and cytochrome P450 3A2 (CYP3A2) protein levels. PTX, a Pgp and CYP3A2 substrate, was administered orally at 20 mg/kg in solution or nanoemulsion either as single agent or upon pretreatment with CUR at 50 mg/kg in tumor-bearing mice. Plasma AUC(0-∞) of PTX administered in nanoemulsion to CUR pretreated mice showed 4.1-fold increase relative to controls. Similarly, relative PTX bioavailability was increased by 5.2-fold, resulting in a 3.2-fold higher PTX accumulation in the tumor tissue. PTX administered in nanoemulsion to CUR pretreated mice also showed significantly enhanced anti-tumor activity. Preliminary safety evaluation showed that CUR + PTX combination did not induce any acute toxicity as measured by body weight changes, blood cell counts, liver enzyme levels, and liver histopathology. The results of this study suggest that combination of PTX and CUR, administered in nanoemulsions, could improve oral bioavailability and therapeutic efficacy in ovarian adenocarcinoma.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Availability; Curcumin; Cytochrome P-450 CYP3A; Emulsions; Enzyme Inhibitors; Female; Humans; Mice; Ovarian Neoplasms; Paclitaxel

Lung cancer is one of the leading causes of cancer-related death worldwide. Curcumin has been reported to have an antitumor effect by inducing apoptosis and suppressing growth of tumor cells. However, the mechanism by which curcumin exerts its anti-cancer effect needs further research. The purpose of the present study was to identify a miRNA-mediated mechanism which plays a role in the anti-cancer effects of curcumin. Alterations in miRNA expression were seen in curcumin-treated A549 cells, including significant downregulation of miRNA-186* expression by microarray analysis and real-time PCR. The miRNA-186* functions by overexpression or inhibition were investigated using biological assays in A549 cells. Additionally, caspase-10 was identified as a target of miRNA-186* using dual luciferase reporter assays and western blot analysis. These results demonstrate that curcumin induces A549 cell apoptosis through a miRNA pathway. Also, miRNA-186* could serve as a potential gene therapy target in curcumin treatment. furthermore, caspase-10 was shown to be a target of miR-186* regulation.

Topics: 3' Untranslated Regions; Adenocarcinoma; Antineoplastic Agents; Apoptosis; Base Sequence; Caspase 10; Cell Growth Processes; Cell Line, Tumor; Curcumin; Down-Regulation; Humans; Lung Neoplasms; Microarray Analysis; MicroRNAs; Signal Transduction

Several studies have shown that curcumin can induce apoptosis and inhibit growth in human A549 lung adenocarcinoma cells. However, the mechanism is not completely understood yet. In the present study, we investigated the in vitro effect of curcumin on cell viability, apoptosis and disorganization of the actin cytoskeleton in A549 cells. Our results showed that curcumin significantly inhibited the viability of A549 cells in a dose- and time-dependent manner by induced apoptosis. The apoptotic process was associated with a disorganization of the architecture of actin microfilaments and a decrease in the levels of F-actin. DMSO-treated control cells exhibited a well-defined F-actin network that was mainly organized into stress fibers. The actin fibers in cells treated with curcumin or the positive control drug cytochalasin B were disorganized, disassembled, or disrupted, however, the disorganization of actin fibers and apoptosis could be prevented by phalloidin, an F-actin stabilizing compound. Thus, these results demonstrated that actin filament disorganization might play a central role in the curcumin-induced apoptosis of A549 cells.

Topics: Actin Cytoskeleton; Actins; Adenocarcinoma; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Line, Tumor; Cell Survival; Curcuma; Curcumin; Cytochalasin B; Cytoskeleton; Dose-Response Relationship, Drug; Humans; Lung Neoplasms; Phalloidine; Phytotherapy; Plant Extracts; Poisons

Curcumin (diferuloylmethane), is a natural chemopreventive agent known to inhibit the proliferation of several cancer cell lines. It has been previously demonstrated that curcumin is a potent inhibitor of EGF-receptor (EGFR) tyrosine kinase, but its inhibitive effect on p21-activated kinase 1 (PAK1), a downstream protein of EGFR, has not been defined. In this paper we found that curcumin repressed the expression of HER2 and inhibited the kinase activity of PAK1 without affecting its expression. Silencing HER2 in gastric cancer cells showed that even if PAK1 activity was transiently strengthened by EGF, curcumin still had a strong inhibitive effect. It should be emphasized that kinase assay in vitro showed that curcumin could act as an ATP-competitive inhibitor, which was supported by computer-aided molecular modeling. Curcumin also downregulated the mRNA and the protein expression of cyclin D1 and suppressed transition of the cells from G(1) to S phase. Therefore, curcumin inhibited the proliferation and invasion of gastric cancer cells. Overall, these results provided novel insights into the mechanisms of curcumin inhibition of gastric cancer cell growth and potential therapeutic strategies for gastric cancer.

Topics: Adenocarcinoma; Anticarcinogenic Agents; Cell Division; Cell Line, Tumor; Curcumin; Cyclin D1; Down-Regulation; Drug Screening Assays, Antitumor; Gene Expression Regulation, Neoplastic; Genes, erbB-2; Humans; Neoplasm Invasiveness; Neoplasm Proteins; p21-Activated Kinases; Protein Kinase Inhibitors; Receptor, ErbB-2; Stomach Neoplasms

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

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

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

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

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

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

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

Pancreatic cancer is a deadly cancer with limited sensitivity to gemcitabine. Molecular targeting of critical signaling pathways [nuclear factor kappa-B (NF-kappaB), PI3K/AKT, and mitogen-activated protein kinase (MAPK)] in combination with gemcitabine may improve sensitivity. We hypothesize that pancreatic cancer cell genetics and signaling response to treatment correlate with efficacy of gemcitabine-based molecular targeting strategies.. PANC-1, PaCa-2, and BxPC-3 cells were treated with curcumin, LY294002, or PD325901 alone or in combination with gemcitabine. Proliferation was measured by cell counts and enzyme activity by Western blot and electrophoretic mobility shift assay.. Each agent dose-dependently decreased proliferation. All cells decreased NF-kappaB activity with curcumin(24 h) except PaCa-2, MEK activity with PD325901(24 h), and PI3Kinase with LY294002(3 h). However, PI3K rebounded to(PaCa-2) or above (Panc-1,BxPC-3) basal in LY294002-treated cells (24 h). Combinations with gemcitabine resulted in at least additive effects on proliferative inhibition. For PANC-1, curcumin + gemcitabine was nearly synergistic, correlating with gemcitabine-induced NF-kappaB activity. LY294002 + gemcitabine was nearly synergistic in PaCa-2 cells, which showed a lower induction of PI3Kinase activity with LY294002. Finally, gemcitabine + PD325901 was only effective in BxPC-3, which exhibited increased MEK activity with gemcitabine.. These results demonstrate differences in treatment efficacy, which correlate with the cell's signaling response to treatment. Signaling profiles of each tumor may be necessary to determine an optimal chemotherapy for pancreatic cancer.

Topics: Adenocarcinoma; Antimetabolites, Antineoplastic; Antineoplastic Agents; Blotting, Western; Cell Proliferation; Chromones; Curcumin; Deoxycytidine; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Electrophoretic Mobility Shift Assay; Enzyme Inhibitors; Gemcitabine; Humans; MAP Kinase Signaling System; Morpholines; NF-kappa B; Pancreatic Neoplasms; Proto-Oncogene Proteins c-akt; Tumor Cells, Cultured

Prior studies from our laboratory have demonstrated the efficacy of a combined treatment of low doses of dietary agents curcumin and phenylethylisothiocyanate in effectively suppressing prostate cancer in vitro in human prostate cancer PC3 cells as well as in vivo in immunodeficient mice implanted with PC3 cells. Hence, this study was undertaken to examine the potential chemopreventive properties of the two agents against transgenic adenocarcinoma of the mouse prostate.. The efficacy of AIN-76A diet supplemented with 2% curcumin or 0.05% PEITC or a combination of 1% curcumin and 0.025% PEITC for periods of 10 and 16 weeks was tested against adenocarcinoma of the mouse prostate. Immunohistochemistry and Western blot analysis were used to examine the expression of proliferation and apoptotic biomarkers. All statistical tests were two-sided.. Supplementing AIN-76A diet with dietary phytochemicals curcumin or PEITC either alone or in combination, significantly decreased incidence of prostate tumor formation (P = 0.0064). Immunohistochemistry revealed a significant inhibition of high-grade PIN (P = 0.0006, 0.000069, 0.00029 for a treatment period of 10 weeks and P = 0.02582, 0.022179, 0.0317 for a treatment period of 16 weeks) along with decreased proliferation and increased apoptotic index in the curcumin, PEITC or curcumin and PEITC treated animals, respectively. Furthermore, Western blot analysis revealed that downregulation of the Akt signaling pathway may in part play a role in decreasing cell proliferation ultimately retarding prostate tumor formation.. Our data lucidly evidence the chemopreventive merits of dietary phytochemicals curcumin and PEITC in suppressing prostate adenocarcinoma.

Topics: Adenocarcinoma; Animals; Anticarcinogenic Agents; Apoptosis; bcl-Associated Death Protein; Caspase 3; Cell Proliferation; Curcumin; Diet; Disease Models, Animal; Drug Therapy, Combination; Forkhead Box Protein O1; Forkhead Transcription Factors; Isothiocyanates; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Prostatic Intraepithelial Neoplasia; Prostatic Neoplasms; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Pyruvate Dehydrogenase Acetyl-Transferring Kinase; Signal Transduction; Time Factors

This study is the first to investigate Calebin-A, a natural compound present in Curcuma longa, which inhibits cell growth and induce apoptosis in SGC7901/VINCRISTINE cells, a multidrug resistant (MDR) human gastric adenocarcinoma cell line. Our data suggest the drug efflux function of P-glycoprotein was inhibited by Calebin-A treatment, while the expression level of P-glycoprotein was not affected. Additionally, co-treatment of Calebin-A and vincristine resulted in a remarkable reduction in S phase and G2/M phase arrest in SGC7901/VINCRISTINE cells. Calebin-A was also found to modulate the activities of mitogen-activated protein kinase (MAPK) family members, which includes decreased c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and increased protein kinase of 38 kDa (p38) activity. These results suggest that Calebin-A might be an effective compound for the treatment of human gastric and other MDR cancers.

Topics: Adenocarcinoma; Antineoplastic Agents, Phytogenic; Apoptosis; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cell Cycle; Cell Line, Tumor; Cinnamates; Curcuma; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Therapy, Combination; Gene Expression Regulation, Neoplastic; Humans; Mitogen-Activated Protein Kinases; Monoterpenes; Stomach Neoplasms; Vincristine

Radix curcumae is a Chinese medicinal herb commonly used in the treatment of malignancy. This study was to investigate the chemopreventive effect of an extract solution from radix curcumae in a rat model of gastric cancer induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG).. Eighty male Wistar rats were randomly allocated to 5 groups administered different agents for 40 weeks: group A, water and normal saline; group B, MNNG and normal saline; group C, MNNG and celecoxib; group D, MNNG and low-dose (1 g/ml) radix curcumae steam distillation extract solution; group E, MNNG and high-dose (2 g/ml) radix curcumae wet distillation extract solution. At the end of week 40, all rats alive were sacrificed. Gastric cancer and precancerous lesions in the stomach were evaluated by histology.. In total there were 35 deaths during the study period. The incidences of gastric cancer were 0.0% (0/16) in group A, 44.4% (7/16) in group B, 12.5% (2/16) in group C, 12.5% (2/16) in group D and 12.5% (2/16) in group E. Tumor incidence and tumor volume were significantly lower in groups C, D and E compared to those in group B (p < 0.05). There was no significant difference of tumor incidence and tumor volume among groups C, D and E (p = 1.000).. Extract solution from radix curcumae obtained by the steam distillation procedure has a chemopreventive effect on gastric cancer induced by MNNG in rats.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents, Phytogenic; Curcuma; Male; Phytotherapy; Plant Extracts; Plant Roots; Rats; Rats, Wistar; Stomach; Stomach Neoplasms

Curcumin has been demonstrated to have an anti-tumor activity but the underlying molecular mechanisms are not fully uncovered. The present study was undertaken to determine the effect of curcumin on the expression of the proto-oncogene Ets-1 and the anti-apoptotic molecule Bcl-2 in human endometrial adenocarcinoma HEC-1-A cells.. Confluent HEC-1-A cells were treated with curcumin at various doses for 16 h or at 60 microM for various time points. At the end of the designated treatments, changes in cell morphology, DNA fragmentation and protein contents of Ets-1 and Bcl-2 were determined, respectively, by light microscopy, DNA laddering assay and Western blot analysis. As an initial step towards understanding whether Ets-1 was a possible up-stream regulator of Bcl-2 expression in HEC-1-A cells and if so, whether curcumin could attenuate the Ets-1-induced up-regulation of Bcl-2 expression, cells were transiently transfected with an Ets-1/GFP (Green Fluorescence Protein) fusion construct and the transfectants were treated with 60 microM curcumin for 16 h, followed by whole cell lysate preparation for Western blot analysis of Bcl-2 protein contents.. Curcumin induced apoptosis-like morphological changes and DNA degradation and decreased basal levels of Ets-1 and Bcl-2 protein contents in HEC-1-A cells in a time- and dose-dependent manner. Overexpression of Ets-1 in the cell resulted in an increase in Bcl-2 protein contents and that increase was attenuated by curcumin treatment.. Curcumin down-regulates Ets-1 and Bcl-2 expression and induces apoptosis in HEC-1-A cells, suggesting a novel molecular mechanism for the anti-tumor activity of curcumin.

Topics: Adenocarcinoma; Antineoplastic Agents; Apoptosis; Curcumin; Down-Regulation; Endometrial Neoplasms; Female; Humans; Proto-Oncogene Mas; Proto-Oncogene Protein c-ets-1; Proto-Oncogene Proteins c-bcl-2; Transfection; Up-Regulation

Gemcitabine, the first-line agent in pancreatic adenocarcinoma, has shown limited clinical benefit. Cyclooxygenase-2 (COX-2) represent one of the most promising targets for cancer prevention and treatment. In this study, we investigated whether the phytochemical curcumin, a natural COX-2 inhibitor, can potentiate gemcitabine effect on survival of human pancreatic cancer cells.. P34 (high COX-2 expression) and Panc-1 (low COX-2 expression) pancreatic cancer cell lines were exposed to different concentrations of gemcitabine (0.1-10 microM), curcumin (0-50 microM), and their combination. Cell viability was evaluated by XTT assay. Cell cycle and apoptosis were assessed by flow cytometry. COX-2, EGFR, and p-ERK1/2 expression was measured by Western blot analysis.. Curcumin increased the inhibitory effect of gemcitabine on cell viability as well as its pro-apoptotic effect in COX-2 positive, p34 cells, but not in COX-2 negative, Panc-1 cells. In p34 cells, combination of curcumin and gemcitabine downregulated both COX-2 and p-ERK1/2 in a dose-dependent manner.. The increased cytotoxic effect of the combination on cell survival and on the induction of apoptosis in COX-2 expressing pancreatic cancer cells is probably associated with downregulation of COX-2 and p-ERK1/2 levels. This finding may contribute to the development of an effective treatment of pancreatic adenocarcinoma.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Cell Survival; Curcumin; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Deoxycytidine; Drug Synergism; Gemcitabine; Humans; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Pancreatic Neoplasms

Turmeric, the powdered dry rhizome of the Curcuma longa plant, and curcumin, the major anti-oxidant constituent of turmeric, have been shown to possess chemopreventive activity. To elucidate the possible interaction of turmeric and curcumin with conjugation reactions, which in many cases are involved in the activation of procarcinogens, we measured their effects in the conjugation of 1-naphthol in Caco-2 cells, a human colon carcinoma cell line, within a 24 h period. Turmeric exhibits inhibitory activity toward both sulfo- and glucuronosyl conjugations of 1-naphthol at approximately the same levels (IC(50)=0.24 and 0.29 mg/ml, respectively). Curcumin inhibits sulfo-conjugation at lower concentrations (IC(50)=9.7 microg/ml), but only showed weak inhibition toward glucuronosyl conjugation of 1-naphthol in Caco-2 cells. In addition, turmeric was found to strongly inhibit in vitro phenol sulfotransferase (SULT) activity and demonstrate moderate inhibitory properties against UDP-glucuronosyl transferase (UGT) activity in Caco-2 cells (IC(50)=0.17 mg/ml and 0.62 mg/ml, respectively). Curcumin also strongly inhibits in vitro phenol sulfotransferase activity with an IC(50) of 2.4 microg/ml. Moreover, and in contrast to the moderate inhibition of UGT activity by turmeric and curcumin, both induce the expression of the UGT1A1 and UGT1A6 genes, revealed by real-time PCR analysis. These findings are indicative of a possible interaction of both turmeric and curcumin with conjugation reactions in the human intestinal tract and colon. This in turn may affect the bioavailability of therapeutic drugs and toxicity levels of environmental chemicals, particularly procarcinogens.

Topics: Adenocarcinoma; Cell Line, Tumor; Colonic Neoplasms; Curcuma; Curcumin; Gene Expression Regulation, Enzymologic; Glucuronides; Humans; Kinetics; Naphthols

Curcumin is a well-known chemopreventive agent of oral cancers as well as stomach and intestinal cancers. The relationship between reactive oxygen species (ROS) production and cell membrane mobility was investigated to clarify the pro-oxidant mechanism of curcumin and tetrahydrocurcumin (TH-curcumin).. The intracellular ROS production and membrane mobility by curcumin or TH-curcumin were measured in human submandibular adenocarcinoma cells (HSGs) and human primary gingival fibroblasts (HGFs). ROS and mobility were measured by 5-(and -6)-carboxy-2',7'-dichlorofluorescein diacetate staining and fluorescence recovery after photo bleaching, respectively.. Curcumin produced ROS dose-dependently. ROS appeared in the region surrounding the cell membrane. The membrane mobility coefficient of the curcumin-treated cells was significantly lower than that of control cells. The lowered membrane mobility induced by curcumin was reversed by the addition of glutathione, an antioxidant. In contrast, TH-curcumin did not affect the ROS production or the membrane mobility coefficient. The alternations induced by curcumin treated HSG cells were greater than those by HGF cells.. The reduction in membrane mobility induced by curcumin was attributed to ROS production. The oxidative effects of curcumin may be related to the structure of the alpha, beta-unsaturated carbonyl moiety as well as the phenolic OH group of this compound.

Topics: Adenocarcinoma; Anticarcinogenic Agents; Antioxidants; Cell Line, Tumor; Cells, Cultured; Curcumin; Dose-Response Relationship, Drug; Fibroblasts; Fluorescence Recovery After Photobleaching; Gingiva; Humans; Membrane Fluidity; Molecular Structure; Oxidants; Reactive Oxygen Species; Submandibular Gland Neoplasms

Adenocarcinoma of the Pancreas is a leading cause of cancer-related mortality, accounting for an estimated 30,000 deaths per year in the United States. Multiple studies have indicated that specific cyclooxygenase-2 (COX-2) inhibitors may serve in the prevention and treatment of a variety of malignancies including pancreatic adenocarcinoma. Recent studies had shown that the long-term use of high concentration of COX-2 inhibitors is not toxic free and may be limited due to serious gastrointestinal and cardiovascular side effects. The chemopreventive efficacy of the phytochemical, curcumin has been demonstrated in several in vitro and animal models. In this study we investigated whether curcumin potentiates the growth inhibition effect of a COX-2 inhibitor (celecoxib, Pfizer, NY, USA) in human pancreatic cancer cells.. P-34 (expressing high levels of COX-2), and MIAPaCa (expressing low levels of COX-2) and Panc-1 (no expression of COX-2) evaluated cell lines were exposed to different concentrations of celecoxib (0-40 microM), curcumin (0-20 microM) and their combination. Cell viability was by XTT assay. Apoptosis was assessed by flow cytometry and COX-2 expression was measured by Western blotting analysis.. In P-34 cells, curcumin synergistically potentiated the inhibitory effect of celecoxib on cell growth. The growth inhibition was associated with inhibition of proliferation and induction of apoptosis. Western blot analysis showed that COX-2 expression was down-regulated by the combination therapy.. Curcumin synergistically augments the growth inhibition inserted by celecoxib in pancreatic cancer cells expressing COX-2. The synergistic effect was mediated through inhibition of COX-2. This may enable the use of celecoxib at lower and safer concentrations and may pave the way for a more effective treatment in this devastating disease.

Topics: Adenocarcinoma; Antineoplastic Agents; Apoptosis; Blotting, Western; Celecoxib; Cell Line, Tumor; Cell Survival; Curcumin; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Diet; Drug Synergism; Flow Cytometry; Humans; Pancreatic Neoplasms; Pyrazoles; Sulfonamides

Cell migration is essential for invasive and metastatic phenotypes of cancer cells. Potential chemopreventive agents of cancer-sulindac sulfide, caffeic acid phenethyl ester (CAPE), curcumin, and (+)-catechin-have been reported to interfere with several types of intracellular signaling. In this study, we examined the effects of these agents on transforming growth factor-beta(TGF-beta)-induced motility and Akt phosphorylation in A549 cells. Judged by gold particle phagokinesis assay, sulindac sulfide, CAPE, and curcumin suppressed the motility of A549 cells promoted by TGF-beta. LY294002, a specific inhibitor of phosphatidylinositol 3-kinase(PI3K)/Akt signaling, also suppressed TGF-beta-induced motility and Akt phosphorylation. Sulindac sulfide and CAPE, but not curcumin, suppressed TGF-beta-induced Akt phosphorylation. We conclude that sulindac sulfide and CAPE suppress the motility promoted by TGF-beta in lung adenocarcinoma cells through the suppression of Akt. Our observations raise the possibility that these agents, except for (+)-catechin, can be applied not only as chemopreventive agents but also as anti-metastatic therapy.

Topics: Adenocarcinoma; Antineoplastic Agents; Caffeic Acids; Catechin; Cell Movement; Curcumin; Humans; Lung Neoplasms; Neovascularization, Pathologic; NF-kappa B; Phenylethyl Alcohol; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Sulindac; Transforming Growth Factor beta; Tumor Cells, Cultured

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

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

Curcumin, a phenolic compound from the rhizome of the plant Curcuma longa has anti-inflammatory, antioxidant and anti-cancer activities. Although the precise mode of action of this compound is not yet elucidated, studies have shown that chemo-preventive action of curcumin might be due to its ability to induce apoptosis and to arrest cell cycle. This study investigated the cellular and molecular changes induced by curcumin leading to the induction of apoptosis in human lung cancer cell lines-A549 and H1299. A549 is p53 proficient and H1299 is p53 null mutant. The lung cancer cells were treated with curcumin (0-160 microM) for 12-72 h. Curcumin inhibited the growth of both the cell lines in a concentration dependent manner. Growth inhibition of H1299 cell lines was both time and concentration dependent. Curcumin induced apoptosis in both the lung cancer cell lines. A decrease in expression of p53, bcl-2, and bcl-X(L) was observed after 12 h exposure of 40 microM curcumin. Bak and Caspase genes remained unchanged up to 60 microM curcumin but showed decrease in expression levels at 80-160 microM. The data also suggest a p53 independent induction of apoptosis in lung cancer cells.

Topics: Adenocarcinoma; Apoptosis; Cell Line, Tumor; Cell Survival; Curcumin; Genes, myc; Humans; Lung Neoplasms; Poly(ADP-ribose) Polymerases; Tumor Suppressor Protein p53

To investigate the mechanism of anti-tumor effects of curcumin on human lung cancer cell (A549).. MTT colorimetry method, fluoroscope, FCM combine PI and Annexin V-FITC double pigmentation method and Western blot method were used.. Under the effect of the curcumin, cell grew against the wall and suspended in the culture liquid, the A549 cell nucleolus were found fragmentated into different size of apoptosis body under fluoroscopy. The cell proliferation were obvious suppressed after treated with different concentration curcumin for 72 hours. The IC50 were 18 micromol/L by using linear regression. The apoptosis induced by curcumin of A549 cell is concentration dependent. With curcumin increased from 5 micromol/L to 30 micromol/L, Annexin-FITC single positive cell (early apoptosis cell) increased from 3.4% to 59.1%. When curcumin concentration reached 40 micromol/L, PI and Annexin V-FITC double positive cell (secondary apoptosis necrosis cell) became major part of cells, and the cell showed G2 phase block. Observed with western blot method, with the increase of curcumin concentration to 10 micromol/L, the expression of PARP increased simultaneously.. Curcumin can interfere cell growth cycle of A549 cell and suppress cell growth. The suppression effect is concentration dependent. The effect depends not only from the nonspecific cytotoxic but also from induced cell apoptosis.

Topics: Adenocarcinoma; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Cycle; Cell Proliferation; Curcumin; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Flow Cytometry; Humans; Lung Neoplasms; Poly(ADP-ribose) Polymerases; Tumor Cells, Cultured

The effects of curcumin on angiogenesis were studied.. Proliferation of bovine aortic endothelial cells (BAECs) and cells of human cancerous cell line SGC-7901 were measured by MTT colorimetric assay after treated by various concentrations of curcumin. The effects of curcumin on BAECS proliferation promoted by tumor conditioned medium were observed by MTT colorimetric assay. The effects of various concentration of curcumin on the migration of BAECs and migration promoted by tumor conditioned medium were investigated by agorose assay.. Curcumin can obviously inhibit the proliferation of BAECs induced by fetal bovine serum (FBS) and tumor conditioned medium. Curcumin can also obviously inhibit the migration of BAECs induced by FBS and tumor conditioned medium.. Curcumin can inhibit angiogenesis by preventing proliferation and migration of endothelial cells. It also suggestes that curcumin is one kind of specific inhibitors of angiogenesis.

Topics: Adenocarcinoma; Angiogenesis Inhibitors; Animals; Aorta; Cattle; Cell Division; Cell Movement; Cells, Cultured; Curcuma; Curcumin; Endothelial Cells; Endothelium, Vascular; Humans; Neovascularization, Pathologic; Plants, Medicinal; Stomach Neoplasms; Tumor Cells, Cultured

To investigate the inhibiting effect of Aining on the human gastric cancer cells.. Morphological and MTT methods were adopted to explore the inhibiting effect of Aining and cisplatin (DDP) on the proliferation of SGC-7901 cancer cell.. Apoptotic morphological changes were seen after the cells cultured with Aining and DDP; inhibiting rate of 1 g/L Aining group was 51%, which had no significant differences with the inhibiting rate 53% of the 25 mg/L DDP group. But both the Aining and the DDP groups were significantly different from the blank group (P < 0.01).. Not only DDP but also Aining could inhibit the proliferation activity of the human gastric cancer cells, and the traditional Chinese medicine compound prescription Aining is very likely to become a new medicine which is utilized to inhibit cancer.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Cell Division; Cisplatin; Curcuma; Drug Combinations; Drugs, Chinese Herbal; Humans; Leeches; Materia Medica; Panax; Plants, Medicinal; Stomach Neoplasms; Tumor Cells, Cultured

Recent evidence supports the theory that tumor growth in vivo depends on evasion of normal homeostatic control mechanisms that operate through induction of cell death by apoptosis. This study tested the hypothesis that several potential chemopreventive agents share the ability to induce apoptosis and that inhibition of apoptosis is a mechanism of tumor promoters. The present study was designed to investigate whether the chemopreventive properties of sulindac, curcumin, and phenylethyl-3-methylcaffeate (PEMC) and the tumor-promoting activity of 6-phenylhexyl isothiocyanate (PHITC) that were observed in our previous studies are associated with the induction or inhibition of apoptosis in azoxymethane (AOM)-induced colon tumors in male F344 rats. At 5 weeks of age, groups of rats were fed control (modified AIN-76A) diet or diets containing 320 ppm of sulindac, 2000 ppm of curcumin, 750 ppm of PEMC, or 640 ppm of PHITC. At 7 weeks of age, all rats except those intended for vehicle (normal saline) treatment were given AOM (15 mg/kg body weight) once weekly for 2 weeks. To study the effect of sulindac administered during promotion/progression stage, the rats were fed the control diet initially and then fed the experimental diet containing 320 ppm of sulindac 14 weeks after the second AOM treatment. The rats were sacrificed 52 weeks after carcinogen treatment, and their colonic tumors were subjected to histopathological evaluation and the appearance of apoptosis. In the current study, chronic administration of sulindac, curcumin, and PEMC or sulindac given only during promotion/progression significantly increased the apoptotic index (percentage of apoptosis) as compared to administration of the control diet; the apoptotic indices in the control, sulindac, curcumin, and PEMC diets were 8.3, 17.6, 17.7, and 18.5%, respectively, and in sulindac administered during promotion/progression stage, the apoptotic index was 19.1%. However, dietary PHITC blocked the process of apoptosis during colon carcinogenesis. The apoptotic index in PHITC diet was 7.0%. Taken together, our data show that chemopreventive properties of agents are correlated with the degree of apoptosis. Therefore apoptosis seems to be a reliable biomarker for the evaluation of potential agents for cancer prevention.

Topics: Adenocarcinoma; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Apoptosis; Azoxymethane; Biomarkers, Tumor; Caffeic Acids; Carcinogens; Colonic Neoplasms; Curcumin; Isothiocyanates; Male; Rats; Rats, Inbred F344; Sulindac

Curcumin, the active ingredient of the rhizome of the plant turmeric (Curcuma longa Linn), a commonly used spice, prevents cancer in animal tumor models. Its mechanism of action is unknown; curcumin may act by inhibiting arachidonic acid metabolism. To explore the mechanism of curcumin's chemopreventive effect, we studied its role in proliferation and apoptosis in the HT-29 and HCT-15 human colon cancer cell lines. Curcumin dose-dependently reduced the proliferation rate of both cell lines, causing a 96% decrease by 48 hours. No apoptosis was detected. The antiproliferative effect was preceded by accumulation of the cells in the G2/M phase of cell cycle. The effect of curcumin was similar in both cell lines, which, however, differ in their ability to produce prostaglandins. We conclude that curcumin inhibits colon cancer cell proliferation in vitro mainly by accumulating cells in the G2/M phase and that this effect is independent of its ability to inhibit prostaglandin synthesis. The role of curcumin's antiproliferative effect in human colon cancer remains to be established.

Topics: Adenocarcinoma; Apoptosis; Cell Cycle; Cell Division; Chemoprevention; Colonic Neoplasms; Curcumin; Humans; Prostaglandins; Tumor Cells, Cultured

Experiments were conducted by using scrape-loading and dye transfer (SLDT) method to study the gap junction intercellular communication (GJIC) of Chinese hamster lung cells (V79), mouse fibrous cells (Balb/c-3T3), rat liver cells (WB) and human embryonal lung cells (2BS). We also observed the inhibition of the GJIC by TPA and the antagonistic effect of Curcumin derivatives on TPA. The results indicated that V79, WB, 3T3 and 2BS normal cells showed medium level of GJIC, and TPA could inhibit the GJIC to some extents. Curcumin derivatives (91022, 91022-S) could counteract the inhibition of TPA-induced GJIC. It was also found that human lung adenocarcinoma cell (A549) and GLC lacked GJIC, and 91022 could improve the GJIC of A549 cell. It may be related to its anticancer activity.

Topics: 3T3 Cells; Adenocarcinoma; Animals; Antineoplastic Agents; Carcinogens; Cell Communication; Cells, Cultured; Cricetinae; Curcumin; Fetus; Gap Junctions; Humans; Liver; Lung; Lung Neoplasms; Mice; Rats; Tetradecanoylphorbol Acetate; Tumor Cells, Cultured

Topics: Adenocarcinoma; Animals; Anticarcinogenic Agents; Azoxymethane; Carcinogens; Colon; Colonic Neoplasms; Curcumin; Diet; Intestinal Mucosa; Lipoxygenase; Male; Ornithine Decarboxylase; Prostaglandin-Endoperoxide Synthases; Protein-Tyrosine Kinases; Rats; Rats, Inbred F344

Curcumin (diferuloylmethane), a yellow pigment that is obtained from the rhizomes of Curcuma longa Linn., is a major component of turmeric and is commonly used as a spice and food-coloring agent. The inhibitory effects of feeding commercial grade curcumin (77% curcumin, 17% demethoxycurcumin, and 3% bisdemethoxycurcumin) in AIN 76A diet on carcinogen-induced tumorigenesis in the forestomach, duodenum, and colon of mice were evaluated. Administration p.o. of commercial grade curcumin in the diet inhibited benzo(a)pyrene-induced forestomach tumorigenesis in A/J mice, N-ethyl-N'-nitro-N-nitrosoguanidine-induced duodenal tumorigenesis in C57BL/6 mice, and azoxymethane (AOM)-induced colon tumorigenesis in CF-1 mice. Dietary commercial grade curcumin was given to mice at: (a) 2 weeks before, during, and for 1 week after carcinogen administration (during the initiation period); (b) 1 week after carcinogen treatment until the end of the experiment (during the postinitiation period); or (c) during both the initiation and postinitiation periods. Feeding 0.5-2.0% commercial grade curcumin in the diet decreased the number of benzo(a)pyrene-induced forestomach tumors per mouse by 51-53% when administered during the initiation period and 47-67% when administered during the postinitiation period. Feeding 0.5-2.0% commercial grade curcumin in the diet decreased the number of N-ethyl-N'-nitro-N-nitrosoguanidine-induced duodenal tumors per mouse by 47-77% when administered during the postinitiation period. Administration of 0.5-4.0% commercial grade curcumin in the diet both during the initiation and postinitation periods decreased the number of AOM-induced colon tumors per mouse by 51-62%. Administration of 2% commercial grade curcumin in the diet inhibited the number of AOM-induced colon tumors per mouse by 66% when fed during the initiation period and 25% when fed during the postinitiation period. The ability of commercial grade curcumin to inhibit AOM-induced colon tumorigenesis is comparable to that of pure curcumin (purity greater than 98%). Administration of pure or commercial grade curcumin in the diet to AOM-treated mice resulted in development of colon tumors which were generally smaller in number and size as compared to the control group of AOM-treated mice. These results indicate that not only did curcumin inhibit the number of tumors per mouse and the percentage of mice with tumors but it also reduced tumor size. Histopathological examination of the tumors sho

Topics: Adenocarcinoma; Adenoma; Adenoma, Villous; Animals; Azoxymethane; Benzo(a)pyrene; Carcinogens; Colonic Neoplasms; Curcumin; Duodenal Neoplasms; Female; Male; Methylnitronitrosoguanidine; Mice; Stomach Neoplasms