bisdemethoxycurcumin and Adenocarcinoma

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 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

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