Consistent with this concept, doxorubicin treatment induced oxidative stress and p53 accumulation both in vitro and in vivo, and reduction of oxidative stress by NAC treatment paid down doxorubicininduced p53 accumulation in vitro. Because DNA damage is induced by doxorubicin and can be a potent inducer of p53 in other cell types, we examined whether DNA damage mediates doxorubicin induced p53 accumulation in cardiac myocytes. Certainly, doxorubicin therapy induced ATM service and DNA damage, and an kinase inhibitor wortmannin paid off p53 accumulation induced by doxorubicin. These results suggest that doxorubicin induces p53 deposition via oxidative DNA damage ATM process and stabilizes p53 protein, and are consistent with the notion that order Letrozole ATM activated by DNA damage phosphorylates. But, it should be noted that p53 deposition is not totally inhibited by treatment with NAC or wortmannin. It had been also reported that the cardioprotective effects of anti-oxidants aren’t very impressive in human clinical studies. Therefore, oxidative anxiety independent systems may also play a part in doxorubicin induced p53 accumulation. Previous studies demonstrate that doxorubicin therapy triggers Urogenital pelvic malignancy p53 accumulation in-the heart, and reduction of p53 activity attenuates negative effects of doxorubicin, suggesting that p53 plays a part in doxorubicin cardiotoxicity. P53dependent cardiomyocyte apoptosis is thought to play an essential role in doxorubicin cardiotoxicity, since doxorubicin caused myocyte apoptosis was paid off from the inhibition of p53 exercise. Nevertheless, we have recently found that p53 stops the activity of hypoxia inducible factor 1 and Hif 1 dependent coronary angiogenesis in the center under chronic pressure overload, resulting in contractile dysfunction. Now, it was shown that p53 induced inhibition of mTOR exercise mediates serious doxorubicin cardiotoxicity separately of cardiomyocyte apoptosis. These results suggest MAP kinase inhibitor that p53 dependent but apoptosisindependent things may be involved with the pathogenesis of doxorubicin cardiotoxicity. We consequently re considered the function of cardiomyocyte apoptosis in doxorubicin cardiotoxicity using transgenic mice in which cardiomyocyte apoptosis is inhibited by the overexpression of Bcl 2 in the guts, and found that inhibition of myocardial apoptosis somewhat enhanced contractile dysfunction caused by chronic doxorubicin treatment. We also found that doxorubicin treatment did not result inmyocardial hypoxia or decline inmyocyte size. Hence, 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 partly distinct.