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

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dc.contributor.authorCho, Soo-Jeong-
dc.contributor.authorKim, Joo Sung-
dc.contributor.authorKim, Jung Mogg-
dc.contributor.authorLee, Jong Yeul-
dc.contributor.authorJung, Hyun Chae-
dc.contributor.authorSong, In Sung-
dc.date.accessioned2010-04-02-
dc.date.available2010-04-02-
dc.date.issued2008-06-04-
dc.identifier.citationInt J Cancer. 2008 Aug 15;123(4):951-7.en
dc.identifier.issn1097-0215 (Electronic)-
dc.identifier.urihttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18521906-
dc.identifier.urihttps://hdl.handle.net/10371/62388-
dc.description.abstractStatins, 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.en
dc.language.isoenen
dc.publisherWiley-Blackwellen
dc.subjectAnimalsen
dc.subjectApoptosis/*drug effectsen
dc.subjectCASP8 and FADD-Like Apoptosis Regulating Protein/biosynthesis/geneticsen
dc.subjectCaspase 3/metabolismen
dc.subjectCell Growth Processes/drug effectsen
dc.subjectCell Line, Tumoren
dc.subjectColitisen
dc.subjectColonic Neoplasms/*drug therapy/genetics/metabolism/pathologyen
dc.subjectDown-Regulation/drug effectsen
dc.subjectDrug Synergismen
dc.subjectEnzyme Activation/drug effectsen
dc.subjectHCT116 Cellsen
dc.subjectHumansen
dc.subjectHydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacologyen
dc.subjectInhibitor of Apoptosis Proteins/biosynthesis/geneticsen
dc.subjectMaleen
dc.subjectMiceen
dc.subjectMice, Inbred C57BLen
dc.subjectProto-Oncogene Proteins c-bcl-2/biosynthesis/geneticsen
dc.subjectSimvastatin/*pharmacologyen
dc.subjectTumor Necrosis Factor-alpha/pharmacologyen
dc.subjectVascular Endothelial Growth Factor A/biosynthesis/geneticsen
dc.subjectXenograft Model Antitumor Assaysen
dc.subjectbcl-X Protein/biosynthesis/geneticsen
dc.titleSimvastatin induces apoptosis in human colon cancer cells and in tumor xenografts, and attenuates colitis-associated colon cancer in miceen
dc.typeArticleen
dc.contributor.AlternativeAuthor조수정-
dc.contributor.AlternativeAuthor김주성-
dc.contributor.AlternativeAuthor김정목-
dc.contributor.AlternativeAuthor이종열-
dc.contributor.AlternativeAuthor정현채-
dc.contributor.AlternativeAuthor송인성-
dc.identifier.doi10.1002/ijc.23593-
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