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Simvastatin induces apoptosis in human colon cancer cells and in tumor xenografts, and attenuates colitis-associated colon cancer in mice

Cited 143 time in Web of Science Cited 148 time in Scopus
Authors
Cho, Soo-Jeong; Kim, Joo Sung; Kim, Jung Mogg; Lee, Jong Yeul; Jung, Hyun Chae; Song, In Sung
Issue Date
2008-06-04
Publisher
Wiley-Blackwell
Citation
Int J Cancer. 2008 Aug 15;123(4):951-7.
Keywords
AnimalsApoptosis/*drug effectsCASP8 and FADD-Like Apoptosis Regulating Protein/biosynthesis/geneticsCaspase 3/metabolismCell Growth Processes/drug effectsCell Line, TumorColitisColonic Neoplasms/*drug therapy/genetics/metabolism/pathologyDown-Regulation/drug effectsDrug SynergismEnzyme Activation/drug effectsHCT116 CellsHumansHydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacologyInhibitor of Apoptosis Proteins/biosynthesis/geneticsMaleMiceMice, Inbred C57BLProto-Oncogene Proteins c-bcl-2/biosynthesis/geneticsSimvastatin/*pharmacologyTumor Necrosis Factor-alpha/pharmacologyVascular Endothelial Growth Factor A/biosynthesis/geneticsXenograft Model Antitumor Assaysbcl-X Protein/biosynthesis/genetics
Abstract
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.
ISSN
1097-0215 (Electronic)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18521906

https://hdl.handle.net/10371/62388
DOI
https://doi.org/10.1002/ijc.23593
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College of Medicine/School of Medicine (의과대학/대학원)Internal Medicine (내과학전공)Journal Papers (저널논문_내과학전공)
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