title: Synergistic induction of apoptosis by sulindac and simvastatin in A549 human lung cancer cells via reactive oxygen species-dependent mitochondrial dysfunction.
abstract: 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.
authors: Department of Internal Medicine, Institute of Wonkwang Medical Science, Wonkwang University, School of Medicine, Iksan, Jeonbuk 570-749, Republic of Korea.
authors: Ki-Eun
authors: KE
authors: Hwang
authors: Chul
authors: C
authors: Park
authors: Su-Jin
authors: SJ
authors: Kwon
authors: Young-Suk
authors: YS
authors: Kim
authors: Do-Sim
authors: DS
authors: Park
authors: Mi-Kyung
authors: MK
authors: Lee
authors: Byoung-Ryun
authors: BR
authors: Kim
authors: Seong-Hoon
authors: SH
authors: Park
authors: Kwon-Ha
authors: KH
authors: Yoon
authors: Eun-Taik
authors: ET
authors: Jeong
authors: Hak-Ryul
authors: HR
authors: Kim
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D019821:Simvastatin / Q000008:administration & dosage*; D013467:Sulindac / Q000008:administration & dosage*
chemical_list: D017382:Reactive Oxygen Species; D013467:Sulindac; D019821:Simvastatin