Prevention of
lung cancer is more feasible and holds greater promise when different agents are used in combination to target multiple processes during
carcinogenesis. The mechanisms by which non-steroidal anti-inflammatory drugs and
statins inhibit
cancer cell growth and induce apoptosis are not fully understood. This study was designed to investigate
lung cancer chemoprevention through a mechanism-based approach using
sulindac at low doses in combination with
simvastatin. We found that
sulindac-induced cytotoxicity was significantly enhanced in the presence of
simvastatin. The combination of
sulindac and
simvastatin induced more extensive caspase-dependent apoptosis in A549 cells compared to that induced with either drug alone. The combination of
sulindac and
simvastatin also increased the loss of mitochondrial transmembrane potential (∆Ψm) and the cytosolic release of cytochrome c. In addition, ROS generation in cells treated with both
sulindac and
simvastatin was markedly increased compared to cells treated with either
sulindac or
simvastatin alone. The enhancement of ROS generation by
sulindac and
simvastatin was abrogated by pretreatment with NAC, which also prevented apoptosis and
mitochondrial dysfunction induced by
sulindac and
simvastatin. These results suggest that
sulindac and
simvastatin-induced ROS generation in A549
lung cancer cells causes their accumulation in mitochondria, triggering the release of apoptogenic molecules from the mitochondria to the cytosol, and thus leading to
caspase activation and cell death.