Background: Non-steroidal anti-inflammatory drugs (NSAIDs) and statins are potential chemopreventive agents. The mechanism underlying the deregulation of survivin by NSAIDs and statins in non-small cell lung cancer (NSCLC) has not been elucidated. We investigated the synergistic interaction of sulindac and simvastatin in lung cancer cells. Methods: Cell viability was measured by the MTT assay. The expression of apoptotic markers, AKT, and survivin in response to sulindac and simvastatin was examined by western blotting. DNA fragmentation by apoptosis was analyzed by flow cytometry in A549 cells. ROS generation was measured by flow cytometry using H2DCFDA and MitoSOX Red, and the effects of pretreatment with N-acetylcysteine were tested. The effects of AKT on survivin expression in sulindac and simvastatin-treated cells were assessed. Survivin was knocked down or overexpressed to determine its role in apoptosis induced by sulindac and simvastatin. Results: Sulindac and simvastatin synergistically augmented apoptosis and intracellular ROS production in A549 cells. Inhibition of AKT by siRNA or LY294002 inhibited survivin, whereas AKT overexpression markedly increased survivin expression even in the presence of sulindac and simvastatin. In addition, survivin siRNA enhanced sulindac and simvastatin-induced apoptosis. In contrast, survivin upregulation protected against sulindac and simvastatin-induced apoptosis.Background: Non-steroidal anti-inflammatory drugs (NSAIDs) and statins are potential chemopreventive agents. The mechanism underlying the deregulation of survivin by NSAIDs and statins in non-small cell lung cancer (NSCLC) has not been elucidated. We investigated the synergistic interaction of sulindac and simvastatin in lung cancer cells. Methods: Cell viability was measured by the MTT assay. The expression of apoptotic markers, AKT, and survivin in response to sulindac and simvastatin was examined by western blotting. DNA fragmentation by apoptosis was analyzed by flow cytometry in A549 cells. ROS generation was measured by flow cytometry using H2DCFDA and MitoSOX Red, and the effects of pretreatment with N-acetylcysteine were tested. The effects of AKT on survivin expression in sulindac and simvastatin-treated cells were assessed. Survivin was knocked down or overexpressed to determine its role in apoptosis induced by sulindac and simvastatin. Results: Sulindac and simvastatin synergistically augmented apoptosis and intracellular ROS production in A549 cells. Inhibition of AKT by siRNA or LY294002 inhibited survivin, whereas AKT overexpression markedly increased survivin expression even in the presence of sulindac and simvastatin. In addition, survivin siRNA enhanced sulindac and simvastatin-induced apoptosis. In contrast, survivin upregulation protected against sulindac and simvastatin-induced apoptosis.