Piperlongumine Enhances Chemotherapy‐Induced Pancreatic Cancer Cell Death

Abstract

Pancreatic cancer is one of the most deadly cancers with a nearly 95% mortality rate. The large majority of pancreatic cancer patients have mutations in the K‐ras oncogene which contribute to uncontrolled cell proliferation. The poor response of K‐ras mutant tumors to currently available chemotherapy and the extremely low survival rate of pancreatic cancer patients point to a critical need for alternative therapeutic strategies. The use of reactive oxygen species (ROS)‐inducing agents has emerged as an innovative and effective strategy to treat K‐ras mutant cancers. We investigated the effects of a known ROS inducer, piperlongumine (PPLGM), a bioactive agent found in long peppers, alone and in combination with chemotherapeutic agents (gemcitabine and erlotinib) on pancreatic cancer cell viability, survival, and apoptosis. MIA PaCa‐2, PANC‐1 (K‐ras mutant), and BxPC‐3 (wild‐type K‐ras) cells were treated with PPLGM, erlotinib, gemcitabine, and their combinations. Cell survival and apoptosis were assessed by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT), clonogenic survival, and histone‐DNA ELISA assays. The combination of PPLGM, erlotinib, and gemcitabine resulted in a greater reduction in cell viability and induction of apoptosis in all three pancreatic cancer cell lines when compared to any agent alone. These results suggest that the use of PPLGM in combination with chemotherapeutic agents could be a successful strategy for achieving better treatment outcomes in K‐ras mutant pancreatic cancer patients.