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...

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ObjectiveThis retrospective case series study of the effectiveness of electroconvulsive therapy (ECT) augmentation on clozapine-resistant schizophrenia was conducted by EMR review.MethodsClozapine-resistance was defined as persistent psychotic symptoms despite at least 12 weeks of clozapine administration with blood levels over 350 ng/mL in order to rule out pseudo-resistance. Seven in-patients who were taking clozapine and treated with ECT were selected. We analyzed the psychopathology and subscales changed by ECT.ResultsThe average number of ECT sessions was 13.4 (±4.6). Total Positive and Negative Syndrome Scale (PANSS) score was significantly reduced by 17.9 (±12.8) points (p=0.0384) on average, which represented a reduction of 25.5% (±14.3). 71.4% (5/7) of patients were identified as clinical remission, with at least a 20% reduction in PANSS score. PANSS reduction was associated with number of ECT sessions, stimulus level in the final session, and blood clozapine levels before ECT. However, the negative subscale on the PANSS were not reduced by ECT in any patient. We did not observe any persistent adverse cognitive effects.ConclusionThis study supports that ECT augmentation on clozapine-resistant schizophrenia reveals clinically effective and safe. Further research should be done involving a larger number of patients to investigate the effectiveness of clozapine/ECT combination therapy.