Involvement of oxidative stress in simvastatin-induced apoptosis of murine CT26 colon carcinoma cells.
Recent studies have suggested that oxidative stress may play a role in the cytotoxic activity of statins against cancer cells. The objective of this study was to elucidate the role of oxidative stress in the cytotoxicity of simvastatin in murine CT26 colon carcinoma cells and B16BL6 melanoma cells. We found that CT26 cells were more sensitive to simvastatin than B16BL16 cells. Interestingly, exposure to simvastatin causes significant apoptotic cell death and perturbations in parameters indicative of oxidative stress in CT26 cells. Moreover, the increase in oxidative stress parameters and cell death were suppressed by isoprenoids including mevalonolactone, farnesyl pyrophosphate ammonium salt, geranylgeranyl pyrophosphate ammonium salt, and coenzyme Q10, and by antioxidants including N-acetyl cysteine, reduced glutathione, superoxide dismutases (SOD), and catalase (CAT) alone or in combination, but were promoted by an inhibitor of glutathione synthesis, L-buthionine-sulfoximine. The signaling pathway induced by simvastatin breaks down the antioxidant defense system by suppressing the expression of reactive oxygen species scavengers, particularly Mn-SOD, CAT, GPx1, and SESN 3, thereby inducing oxidative stress and apoptotic cell death. Collectively, our results demonstrate that simvastatin induces colon cancer cell death at least in part by increasing intracellular oxidative stress and inducing apoptosis.
Qi
Xu-Feng
XF
Key Laboratory for Regenerative Medicine, Ministry of Education, Jinan University, Guangzhou 510632, People's Republic of China.
Kim
Dong-Heui
DH
Yoon
Yang-Suk
YS
Kim
Soo-Ki
SK
Cai
Dong-Qing
DQ
Teng
Yung-Chien
YC
Shim
Kwang-Yong
KY
Lee
Kyu-Jae
KJ
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005978:Glutathione / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D051379:Mice; D009842:Oligopeptides / Q000494:pharmacology; D018384:Oxidative Stress; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009842:Oligopeptides; D011106:Polyisoprenyl Phosphates; D017382:Reactive Oxygen Species; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; D019328:Buthionine Sulfoximine; D019821:Simvastatin; D051057:Proto-Oncogene Proteins c-akt; D005978:Glutathione; C002963:geranylgeranyl pyrophosphate; D000111:Acetylcysteine