Simvastatin induces apoptosis in human colon cancer cells and in tumor xenografts, and attenuates colitis-associated colon cancer in mice.
Statins, HMG-CoA reductase inhibitors could be associated with the risk reduction of colorectal cancer. We previously demonstrated that simvastatin inhibits NF-kappaB signaling in human intestinal epithelial cells and ameliorates acute murine colitis. The aim of our study was to evaluate the effects of simvastatin on the apoptotic pathways related to NF-kappaB signaling in colon cancer cells, and on anticancer effects in 2 different animal models. We treated cell lines (COLO 205 and HCT 116) with simvastatin or vehicle and determined apoptosis by cell cycle analysis, Annexin V-FITC staining, caspase-3 activity assay and confocal microscopy. We assessed the expression of antiapoptotic factors by RT-PCR and Western blotting. In the colitis-associated colon cancer (CAC) model, we induced colonic tumors in C57/BL6 mice by azoxymethane and dextran sulfate sodium administration, and evaluated simvastatin's effect on tumor growth. In the xenograft model, we evaluated its effect on the inoculated tumor growth. In both cell lines, simvastatin caused dose- and time-dependent cell death. Annexin V staining significantly increased after simvastatin treatment. It augmented caspase-3 activity and downregulated the expression of Bcl-2, Bcl-xL, cIAP1 and cFLIP. In the CAC model, simvastatin significantly reduced tumor development. In the xenograft model, tumors from animals treated with simvastatin had smaller volumes, larger necrotic areas, lower expression of VEGF and higher apoptotic scores. In conclusion, simvastatin inhibited colon cancer development by induction of apoptosis and suppression of angiogenesis. These results suggest that simvastatin could be a potential chemopreventive and therapeutic agent of CAC as well as de novo colon cancer.
Department of Internal Medicine, Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea.
Soo-Jeong
SJ
Cho
Joo Sung
JS
Kim
Jung Mogg
JM
Kim
Jong Yeul
JY
Lee
Hyun Chae
HC
Jung
In Sung
IS
Song
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000096:biosynthesis / Q000235:genetics; D053148:Caspase 3 / Q000378:metabolism; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D003092:Colitis; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D019821:Simvastatin / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D051020:bcl-X Protein / Q000096:biosynthesis / Q000235:genetics
C494811:BCL2L1 protein, human; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D051020:bcl-X Protein; D019821:Simvastatin; D053148:Caspase 3