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Bisdemethoxycurcumin potentiates gemcitabine to induce mitochondrial dysfunctions and apoptosis in human pancreatic adenocarcinoma cells

Pancreatic cancer is a highly aggressive malignancy, gemcitabine is indicated as a standard single agent for the treatment of pancreatic cancer, however it only extends survival by a mere 3–6 weeks. In this present study we investigate whether bisdemethoxycurcumin (BDMC), a derivative of curcumin, potentiates gemcitabine in human pancreatic cancer cells. The result suggested that BDMC produced a synergistic effects with gemcitabine by inducing mitochondrial dysfunctions and apoptosis in PANC‐1 and MiaPaCa‐2 pancreatic cancer cells. By using 2D‐MS, we found 13 essential proteins were significantly changed in response to gemcitabine alone or combined with BDMC. Pharmacological network analysis revealed that glucose‐regulated protein 78 (GRP78) as the hub activated by BDMC. We then demonstrated that BDMC upregulates GRP78 and facilitated apoptosis through eIF2α/CHOP pathway. In addition, DJ‐1 and prohibitin, two identified markers of chemoresistance, were increased by gemcitabine in PANC‐1 cells. This could be reversed by BDMC, suggesting that BDMC partially offsets the chemoresistance induced by gemcitabine. In conclusion, our study shows that BDMC promotes apoptosis through a GRP78‐dependent pathway and mitochondrial dysfunctions, and potentiates the antitumor effect of gemcitabine in human pancreatic cancer cells.