Oxidative Stress by Capsaicin in Cancer

Pancreatic cancer is an aggressive malignancy with poor overall prognosis. As a result, there is a crucial need to identify and develop effective strategies for treatment. Natural bioactive compounds have demonstrated promising chemo-preventive properties against various types of cancers, including pancreatic. The mechanism of capsaicin, a major component of red chili peppers, has been widely studied and proven to exert anti-cancer effects on various cancer cell lines. In this respect, its role in the treatment of pancreatic cancer and its mechanism of action via mitochondrial death-dependent pathway is currently under extensive investigation. Researchers have demonstrated the ability of capsaicin to inhibit the proliferation of various pancreatic cell lines. Apoptosis has been associated with the generation of reactive oxygen species (ROS), activation of JNK, decreased mitochondrial depolarization and release of cytochrome-c, thus leading to activation of caspase-3 cascade. Mitochondria are the major source of ROS, and capsaicin causes an increase in ROS generation through inhibition of mitochondrial complex-I and complex-III activity, as well as ATP levels in pancreatic cancer cell lines. At the same time antioxidant levels of catalase, super-oxide dismutase and glutathione peroxidase also decreased, resulting in oxidative stress and apoptosis. These results are comparable to in vivo studies, where capsaicin-fed mice showed similar effects: a decrease in antioxidant levels leading to oxidative stress and apoptosis. Furthermore, the effect of capsaicin on the interaction of redox-sensitive thioredoxin (Trx) and apoptosis signal-regulating kinase 1 (ASK1) complex was explored in pancreatic cell lines. A novel role of capsaicin was also demonstrated in mediating oxidative stress. Capsaicin was found to inhibit Trx, causing the dissociation of the Trx-ASK1 complex and activation of ASK1-dependent apoptotic pathway in pancreatic tumor cells in both in vitro and in vivo models. This gives rise to a new outlook on the effects of capsaicin on pancreatic cancer treatment and prevention.