it is probable that p53 dependent but apoptosis independent mechanisms also contribute to the pathogenesis of doxorubicin cardiotoxicity. The 3 hydroxy 3 methylglutaryl CoA reductase inhibitors o-r statins are trusted as a lowering drug, and also known to be cardioprotective through lipid lowering separate pleiotropic effects. For instance, statin therapy protects GW0742 against cardiac hypertrophy, ischemia reperfusion injury, stroke, and heart failure in animals. Most of these pleiotropic effects are believed to be mediated by inhibiting the synthesis of isoprenoid intermediates such as farnesyl pyrophosphate and geranylgeranyl pyrophosphate downstream of the mevalonate pathway. GGPP and fpp serve as lipid accessories for that posttranslational modifications of the variety of proteins including small G proteins. Of note, activation of NADPH oxidase needs geranylgeranylation of Rac1, and it had been found that the protective effect of statins against cardiac hypertrophy ismediated by its antioxidant effects relating to the inhibition of Rac1 action. Whether statins exert protective effects against doxorubicin cardiotoxicity by similar mechanisms remains unknown. In this study we investigated how p53 mediates the effects of doxorubicin and how p53 accumulation is induced by doxorubicin. We also examined the potential mechanisms of cardioprotection by statins against doxorubicin. We showthat Infectious causes of cancer doxorubicin cardiotoxicity is attenuated by pitavastatin through the inhibition of Rac1 activity and mediated by oxidative DNA damage ATM p53 apoptosis path. Doxorubicin was from Kyowa Hakko Kogyo. D acetyl L mevalonolactone, cysteine, farnesyl pyrophosphate, geranylgeranyl pyrophosphate, NADPH, and lucigenin were from Sigma. Wortmannin, farnesyltransferase inhibitor, geranylgeranyl transferase inhibitor, Rac1 inhibitor, and apocynin were from Calbiochem. Dihydroethidium and 5 chloromethyl 2?, 7? dichlorodihydrofluorescein diacetate, acetyl ester were from Molecular Probes. Hydrogen peroxide was from Wako. Pitavastatin was supplied by Kowa. Neonatal rat cardiomyocytes were prepared as previously described. Doxorubicin was added to culture media 24 h after planning. ALK inhibitor Where indicated, cells were pre-treated for 30 min using the following compounds: wortmannin, 1 50 uM; NAC, 1 50 uM; pitavastatin, 0. 1 10 uM; mevalonate, 200 uM; GGPP, 10 uM; FPP, 10 uM; GTI, 30 uM; FTI, 20 nM; Rac1 chemical, 100 uM. C57BL/6 mice were purchased from SLC. Heterozygous p53 deficient mice on C57BL/6 back ground were from Jackson Laboratory. For experiments using p53 heterozygous knockout mice, C57BL/6 mice were used as controls.