Despite the observation that prohibitin is upregulated in both http://www.selleckchem.com/products/dorsomorphin-2hcl.html cell lines following lovastatin treatment, an expected down regulation of E2F1 only occurred in Rb positive MDAMB231 cells. Therefore, while acting synergistically Inhibitors,Modulators,Libraries with Rb in the suppression of E2F1, prohibitin does not seem to impair E2F1 expression alone. As for the down stream targets in the E2F mediated pathway, we identi fied changes in both MCM7 and MSH2. Although MCM7 belongs to the cell cycle DNA check points, MSH2 is a representative member of MMR sys tems. The expression of both of these was significantly suppressed by lovastatin. Interestingly, the suppression occurred in both cell lines, suggesting that it may not be mediated exclusively through E2F1 reduction, and that perhaps other regulatory pathways are also affected by lovastatin.

Statin treated breast cancer cells die through apoptosis. It was therefore not surprising that a large Inhibitors,Modulators,Libraries number of identified proteins was associated with the programmed cell death pathway. In addition Inhibitors,Modulators,Libraries to prohibi tin, RhoB and cofilin 1 2, there was also suppression of TRAP 1 and Ku70 expression. Both of these proteins protect the cells from apoptosis and oxidative stress. These data comply with previous reports sug gesting that increased oxidative stress may be a cause of statin induced cytotoxicity in breast cancer. Recently, it has been shown that fluvastatin and simvas tatin enhance NO levels and increase iNOS RNA and protein expression in breast cancer MCF 7 cells, indicat ing that iNOS mediated NO is responsible, in part, for the Inhibitors,Modulators,Libraries proapoptotic, tumoricidal, and antiproliferative effect of statins.

Furthermore, the cell death of MCF 7 cells incubated with N acetyl L cysteine plus statins could almost be reversed, supporting our results that oxidative stress plays an important role Inhibitors,Modulators,Libraries in the cell death induced by statins. In terms of metabolic changes, the downregulation of glycolytical this research enzymes triosephosphate isomerase, alpha enolase and dihydrolipoamide acetyltransferase and tri carboxylic acid cycle enzymes such as SDHA represent potential pathways by which lovastatin may induce cell death through the suppression of energy producing pathways. Glycolysis is the primary energy producing pathway in cancer cells and is therefore a highly valu able target in anti cancer therapy. The changes in enzyme expressions correlate with the NMR based metabolic profiles, decreased production of de novo 13 C lactate, 13C alanine and C4 glutamate and accumu PTEN through an Akt dependant pathway. The lation of intracellular glucose. Due to its close relation to anaerobic glycolysis, we chose to investigate the role of the protein kinase Akt. A downregulation of the active p Akt form was detected in both cell lines.