Modulation of P300 Acetylation to Protect Against Doxorubicin-induced Cardiotoxicity

Doxorubicin is amongst the most widely prescribed chemotherapy drugs, although progressive use increases the risk of heart failure due to cardiotoxicity. In one mechanism, doxorubicin induces cardiomyocyte (CM) death mediated by the tumour suppressor, p53. Currently, there are no preventative treatments for doxorubicin-induced cardiotoxicity, although a number of therapies are being evaluated. To induce CM death, p53 requires acetylation by the histone-acetyltransferase protein, p300. Therefore, we hypothesize that p300-mediated inactivation of p53 protects against doxorubicin-induced cardiotoxicity. In vitro, we evaluated markers of p53 activation, DNA damage, and apoptosis. For experiments in vivo, we assessed survival, heart function, and cardiac tissue morphology. In vitro, p300 inhibition led to reduced p53 activation, DNA damage and apoptosis. In vivo, p300 bromodomain inhibition reduced mortality and improved heart function. These results demonstrate a novel targeted therapy to address the growing issue of doxorubicin cardiotoxicity and may potentiate a new drug for clinical use.M.Sc.2021-06-22 00:00:0