Abstract 16127: The Pivotal Role of p53 in Doxorubicin-Induced Acute versus Chronic Cardiotoxicity

Introduction: Doxorubicin (DOX) is an effective anticancer chemotherapeutic which also induces acute and chronic cardiotoxicities. Inhibition of p53 activity is cardioprotectiveagainst acute cardiotoxicityin adult mice receiving high doses of DOX. However, functional p53 also reduces DOX-induced mitochondrial DNA oxidation. To explain these paradoxical results, we examined the role of p53 in DOX-induced acute and chronic cardiotoxicitywith a clinically relevant juvenile mouse model. Methods: Two week old MHC-CB7 mice (which express dominant-interfering p53 in cardiomyocytes, CMs) and their non-transgenic (NON-TXG) littermates were given weekly DOX injections for 5 weeks (25 mg/kg total dose). Animals were studied 1 week (acute stage) or 13 weeks (late stage) after the last DOX injection. Cardiac function was measured with echocardiography. CM apoptosis was quantified using anti-active caspase-3 staining. The level of p53, Akt (an anti-apoptotic protein), and ataxia telangiectasiamutated (ATM, a marker...