Perillyl alcohol and methyl jasmonate sensitize cancer cells to cisplatin

Breast cancer is the second leading cause of cancer deaths among women in the United States. Several treatment options exist, with different side effects. To alleviate the side effects, several research groups have studied chemotherapeutic effects of plant compounds on cancer cells. These could be used as an alternative treatment option either alone or in combination with other chemotherapeutic drugs. The aim of this study was to evaluate the activity of a combination of perillyl alcohol (POH), methyl jasmonate (MJ) with cisplatin to define the most effective schedule and to investigate the mechanism of action in breast cancer cells. POH and MJ treatment (20% decrease in cell viability concentration) enhanced the cytotoxicity for subsequent exposure to cisplatin in MDA-MB-435 and MDA-MB-231 cells. Combination treatment of POH and MJ blocked cells at the G0/G1 phase of the cell cycle and the addition of cisplatin forced the cells to progress through the cell cycle and induced apoptosis. Apoptotic mechanistic studies indicated that POH and MJ treatment activated tumor necrosis factor receptor 1 and this was further increased by the addition of cisplatin. It was also found that mitochondrial membrane potential decreased with POH and MJ treatment; this effect was further enhanced by cisplatin treatment. These findings contributed to a better understanding of molecular mechanism of apoptosis in combination treatment of POH, MJ, and cisplatin. Results also showed that the combination treatment of three drugs is more effective than single drug alone or two drugs together.