Consistent with this concept, doxorubicin treatment induced oxidative stress and p53 accumulation both in vivo and in vitro, and reduction of oxidative stress by NAC treatment paid off doxorubicininduced p53 accumulation in vitro. Because DNA damage is induced by doxorubicin and can be a powerful inducer of p53 in other cell types, we examined whether DNA damage mediates doxorubicin induced p53 accumulation in cardiac myocytes. Indeed, doxorubicin therapy induced DNA damage and ATM initial, and p53 accumulation was reduced by an ATM kinase inhibitor wortmannin induced by doxorubicin. These findings are consistent with the idea that PFT alpha ATM activated by DNA damage phosphorylates and stabilizes p53 protein, and suggest that doxorubicin induces p53 accumulation via oxidative DNA damage ATM path. However, it must be noted that p53 deposition isn’t totally inhibited by treatment with NAC or wortmannin. It had been also noted the cardioprotective effects of anti-oxidants are not very remarkable in human clinical trials. Hence, oxidative anxiety separate systems may also play a role in doxorubicin induced p53 accumulation. Previous studies demonstrate that doxorubicin therapy causes Lymphatic system p53 accumulation in the heart, and reduced amount of p53 activity attenuates negative effects of doxorubicin, indicating that p53 plays a role in doxorubicin cardiotoxicity. Since doxorubicin caused myocyte apoptosis was paid off by the inhibition of p53 action, p53dependent cardiomyocyte apoptosis has been thought to play an essential role in doxorubicin cardiotoxicity. Nevertheless, we’ve recently shown that p53 inhibits the action of hypoxia inducible factor 1 and Hif 1 dependent coronary angiogenesis in the center under chronic pressure overload, ultimately causing contractile dysfunction. More recently, it was shown that p53 induced inhibition of mTOR action mediates intense doxorubicin cardiotoxicity independently of cardiomyocyte apoptosis. These results suggest Lonafarnib structure that p53 dependent but apoptosisindependent systems could be involved in the pathogenesis of doxorubicin cardiotoxicity. We consequently re examined the role of cardiomyocyte apoptosis in doxorubicin cardiotoxicity using transgenic mice where cardiomyocyte apoptosis is inhibited by the overexpression of Bcl 2 in the heart, and found that inhibition of myocardial apoptosis significantly enhanced contractile disorder caused by chronic doxorubicin treatment. We also discovered that doxorubicin therapy didn’t result inmyocardial hypoxia or reduction inmyocyte size. Thus, we consider that persistent doxorubicin cardiotoxicity is mediated by p53 dependent cardiomyocyte apoptosis. These information collectively suggest that, while both acute and chronic doxorubicin cardiotoxicity are mediated by p53, the downstream effectors of p53 in these two situationsmay be partially different.