Browsing by Subject "Simvastatin"

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Interaction of simvastatin and aerobic exercise on expression of mitochondrial and cardioprotective proteins in skeletal and cardiac muscle tissue
(2006-05) Meaney, Mary Patricia; Starnes, Joseph W.
Simvastatin is a cholesterol-lowering drug designed to lower cholesterol by inhibiting HMG-CoA reductase, the rate-limiting enzyme of cholesterol synthesis. Statins also inhibit the production of coenzyme Q (CoQ), which shares the same biosynthetic pathway. CoQ is an essential part of the mitochondrial electron transport chain (ETC) and has antioxidant properties. In addition, statins have been shown to effect the expression of antioxidant enzymes and heat shock proteins. Aerobic exercise has also been shown to have an effect on the aforementioned proteins. Statins and aerobicexercise are often co-prescribed by physicians even though the interaction of statins and exercise in heart and skeletal muscle has not been adequately explored. Purpose: To determine the interaction of simvastatin and exercise on CoQ, catalase (CAT), glutathione peroxidase (GPx), Manganese superoxide dismutase (Mn SOD), and heat shock protein 70 (HSP70) in cardiac muscle tissue and the expression of CoQ in the plantaris. Methods: Female 4-mo-old Sprague-Dawley rats were randomly assigned to four treatment groups (N = 15-18/group): sedentary (SED), sedentary treated with simvastatin (SED+SIM), exercise trained (EX), and exercise trained treated with simvastatin (EX+SIM). Rats assigned to simvastatin treated groups received 10 mg simvastatin (Zocor®)/kg body/eight/day for four weeks. Rats assigned to exercise groups were exercised on a treadmill five days/week for four weeks at about 70% VO2max for a duration that was gradually increased to 60 minutes/day. Twenty-four hours after the last session, the animals were euthanized and the heart and both plantaris muscles were removed. Some hearts were perfused for 20 minutes to rinse away blood and others were subjected to an ischemia-reperfusion (I-R) protocol. Left ventricles of IR hearts and the left plantaris were homogenized in ddH2O and lipids were extracted and analyzed for CoQ by high performance liquid chromatography. CAT, GPx, and Mn SOD activity was measured polarographically and HSP70 expression was determined by western blotting of the supernatant of homogenate from the left ventricular tissue of rinsed hearts. Results: A simvastatin main effect was observed on CoQ expression of cardiac and skeletal muscle, and CAT activity of cardiac muscle tissue. Expression of CoQ was decreased while CAT activity was increased following statin treatment. An exercise main effect was observed on CoQ and HSP70 expression of cardiac muscle tissue. Exercise decreased CoQ expression, but increased HSP70 expression in the heart. An interaction effect was observed on both HSP70 expression and Mn SOD activity of cardiac tissue. With respect to HSP70, treatment with simvastatin slightly attenuated an exercise induced increase in HSP70 expression. With respect to Mn SOD, treatment with simvastatin or exercise decreased activity while a combined treatment restored Mn SOD activity to a level similar to that of animals who received no treatment. Conclusion: Treatment with simvastatin or exercise alone results in alterations in the expression of CoQ and HSP70 and activity of CAT, GPx, and Mn SOD. With co-administration, simvastatin and aerobic exercise interact in such a way that maintains one's antioxidant defenses despite impairment the body's ability to synthesize CoQ.
Targeting breast cancer with natural forms of vitamin E and simvastatin
(2012-05) Gopalan, Archana; Kline, Kimberly; Sanders, Bob G.; Hursting, Stephen; Tucker, Philip; deGraffenried, Linda
Breast cancer is the second leading cause of death due to cancer in women. A number of effective therapeutic strategies have been implemented in clinics to cope with the disease yet recurrent disease and toxicity reduce their effectiveness. Hence, there is a need to identify and develop more effective therapies with reduced toxic side effects to improve overall survival rates. This dissertation investigates the mechanisms of action of two natural forms of vitamin E and a cholesterol lowering drug, simvastatin, as a therapeutic strategy in human breast cancer cells. Vitamin E in nature consists of eight distinct forms which are fat soluble small lipids. Until recently, vitamin E was known as a potent antioxidant but emerging work suggests they may be resourceful agents in managing a number of chronic diseases including cancer. Anticancer properties of vitamin E have been identified to be limited to the γ- and δ- forms of both tocopherols and tocotrienols. Gamma-tocopherol ([gamma]T) and gamma-tocotrienol ([gamma]T3) have both already been identified to induce death receptor 5 (DR5) mediated apoptosis in breast cancer cells. Studies here show that similar to [gamma]T3, [gamma]T induced DR5 activation is mediated by c-Jun N-terminal kinase/C/EBP homologous protein (JNK/CHOP) proapoptotic axis which in part contributed to [gamma]T mediated dowregulation of c-FLIP, Bcl-2 and Survivin. Also, both agents activate de novo ceramide synthesis pathway which induces JNK/CHOP/DR5 proapoptotic axis and downregulates antiapoptotic factors FLICE inhibitory protein (c-FLIP), B-cell lymphoma 2 (Bcl-2) and Survivin leading to apoptosis. Simvastatin (SVA) has been identified to display pleiotropic effects including anticancer effects but mechanisms responsible for these actions have yet to be fully understood. In this dissertation, it was observed that simvastatin induced apoptosis in human breast cancer cells via activation of JNK/CHOP/DR5 proapoptotic axis and down regulation of antiapoptotic factors c-FLIP and Survivin which are in part dependent on JNK/CHOP/DR5 axis. The anticancer effects mediated by simvastatin can be reversed by exogenously added mevalonate and geranylgeranyl pyrophosphate (GGPP), implicating the blockage of mevalonate as a key event. Furthermore, work has been done to understand the factors responsible for drug resistance and identify therapeutic strategies to counteract the same. It was observed that development of drug resistance was associated with an increase in the percentage of tumor initiating cells (TICs) in both tamoxifen and Adriamycin resistant cells compared to their parental counterparts which was accompanied by an increase in phosphorylated form of Signal transducer and activator of transcription 3 (Stat3) proteins as well as its downstream mediators c-Myc, cyclin D1, Bcl-xL and Survivin. Inhibition of Stat3 demonstrated that Stat3 and its downstream mediators play an important role in regulation of TICs in drug resistant breast cancer. Moreover, SVA, [gamma]T3 and combination of SVA+[gamma]T3 has been observed to target TICs in drug resistant human breast cancer cells and downregulate Stat3 as well as its downstream mediators making it an attractive agent to overcome drug resistance. From the data presented here, the mechanisms responsible for the anticancer actions of [gamma]T, [gamma]T3 and SVA have been better understood, providing the necessary rationale to test these agents by themselves or in combination in pre-clinical models.