Abstract
We evaluated the mechanism of capsaicin-mediated ROS generation in pancreatic cancer cells. The generation of ROS was about 4–6 fold more as compared to control and as early as 1 h after capsaicin treatment in BxPC-3 and AsPC-1 cells but not in normal HPDE-6 cells. The generation of ROS was inhibited by catalase and EUK-134. To delineate the mechanism of ROS generation, enzymatic activities of mitochondrial complex-I and complex-III were determined in the pure mitochondria. Our results shows that capsaicin inhibits about 2.5–9% and 5–20% of complex-I activity and 8–75% of complex-III activity in BxPC-3 and AsPC-1 cells respectively, which was attenuable by SOD, catalase and EUK-134. On the other hand, capsaicin treatment failed to inhibit complex-I or complex-III activities in normal HPDE-6 cells. The ATP levels were drastically suppressed by capsaicin treatment in both BxPC-3 and AsPC-1 cells and attenuated by catalase or EUK-134. Oxidation of mitochondria-specific cardiolipin was substantially higher in capsaicin treated cells. BxPC-3 derived ρ0 cells, which lack mitochondrial DNA, were completely resistant to capsaicin mediated ROS generation and apoptosis. Our results reveal that the release of cytochrome c and cleavage of both caspase-9 and caspase-3 due to disruption of mitochondrial membrane potential were significantly blocked by catalase and EUK-134 in BxPC-3 cells. Our results further demonstrate that capsaicin treatment not only inhibit the enzymatic activity and expression of SOD, catalase and glutathione peroxidase but also reduce glutathione level. Over-expression of catalase by transient transfection protected the cells from capsaicin-mediated ROS generation and apoptosis. Furthermore, tumors from mice orally fed with 2.5 mg/kg capsaicin show decreased SOD activity and an increase in GSSG/GSH levels as compared to controls. Taken together, our results suggest the involvement of mitochondrial complex-I and III in capsaicin-mediated ROS generation and decrease in antioxidant levels resulting in severe mitochondrial damage leading to apoptosis in pancreatic cancer cells.
Highlights
Pancreatic cancer is one of the most deadliest of all the solid malignancies in the United States [1]
Our current results shows that capsaicin induced apoptosis in BxPC-3 and AsPC-1 cells but not in HPDE-6 cells was associated with reactive oxygen species (ROS) generation
The ROS generation by capsaicin was due to marked inhibition of mitochondrial electron transport chain (ETC) complexes-I and III and downregulation of antioxidants such as GSH, catalase, superoxide dismutase (SOD) and glutathione peroxidase (GPx) indicating the involvement of mitochondria
Summary
Pancreatic cancer is one of the most deadliest of all the solid malignancies in the United States [1]. Pancreatic cancers generally respond poorly to conventional treatment modalities such as chemotherapy and radiation therapy [2]. There is no consensus regarding optimal therapeutic agents in pancreatic cancer, the development of novel approaches to prevent and treat pancreatic cancer is an important mission. Epidemiological studies continue to support the premise that diet rich in fruits, vegetables and some spices may be protective against various human malignancies including pancreatic cancer and that consumption of chili peppers may protect against gastrointestinal-related cancers [4,5,6,7,8,9,10]
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