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

Abstract

Statins, HMG-CoA reductase inhibitors could be associated with the risk reduction of colorectal cancer. We previously demonstrated that simvastatin inhibits NF-jB 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-jB 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. ' 2008 Wiley-Liss, Inc.Key words: simvastatin; apoptosis; colon cancer cells; tumor xenograft; colitis-associated colon cancer Statins are 3-hydroxy-3-methyl-glutaryl coenzyme A (HMGCoA) reductase inhibitors that reduce cholesterol synthesis by preventing conversion of HMG-CoA to mevalonate. Besides their lipid-lowering effect, increasing evidence suggests that statins have therapeutic effects in a wide variety of diseases including cancer. [1][2][3][4] Statins suppress inflammation, 5,6 modulate angiogenesis, 7-9 and inhibit the growth of a wide spectrum of cell lines. [1][2][3][10][11][12] Moreover, statins are associated with a reduced risk of colorectal cancer (CRC). 13 The mechanisms for all of those effects, however, remain unclear.We recently demonstrated that simvastatin inhibits NF-jB signaling in human intestinal epithelial cells and ameliorates acute murine colitis. 6 Moreover, NF-jB activation plays a critical role in the development of colitis-associated colon cancer (CAC) and inflammation-driven tumor progression in other mouse models. 14,15 Because NF-jB as a transcription factor has been linked to tumorigenesis, apoptosis, inflammation and angiogenesis, 16 we hypothesized that simvastatin may mediate their anti-CRC effects by modulating NF-jB pathway.In our study, we evalua...

Pravastatin induces cell cycle arrest and decreased production of VEGF and bFGF in multiple myeloma cell line

“…The reduction of VEGF and FGF was observed by others (Cho et al, 2008) who note the reduction of VEGF in vitro and in vivo. Several studies shows (Zhong et al, 2011) that statins reduce mRNA of FGF, HGF and TGFβ in osteosarcoma cells in culture.…”

Prognostic significance of monocarboxylate transporter 4 expression in patients with colorectal cancer

“…Quercetin and simvastatin inhibit human MCT1 and human MCT4, respectively. Simvastatin has been studied for the treatment of several malignancies, such as colon cancer, prostate cancer and chronic lymphocytic leukemia (32)(33)(34)(35). In fact, a phase II study of simvastatin plus irinotecan, 5-fluoruracil and leucovorin as first-line chemotherapy has been carried out (33).…”

C35 is overexpressed in colorectal cancer and is associated tumor invasion and metastasis

“…This indicates the potential for using GGTase-I inhibitors in CRC therapy. A point worth noting is that stains like simvastatin are capable of inhibiting the proliferation and migration of colon cancer cells (14,15), while geranylgeraniol, which can be taken up by cells and converted to geranylgeranyl diphosphate, may reverse the anti-tumor effects of stains (15). These findings suggest that the effects of stains on colon cancer cells might be mediated by interfering with geranylgeranylation of certain proteins.…”