The discovery of doxorubicin (Dox; Adriamycin) an antitumor antibiotic more than 40 years ago lead to a major step in the fight against cancer. The agent was found to be effective for the treatment of many cancers especially breast cancer and leukemia. Unfortunately, its clinical use is limited by life threatening dose-dependent cardiac side effects that lead to degenerative cardiomyopathy followed by congestive heart failure. New drugs have emerged from recent research efforts, but Dox still remains a major component of the therapeutic armamentarium because of its high efficacy. The overall aim of this proposal is to elucidate the molecular genetic mechanisms of Dox toxicity. Our studies have demonstrated that Dox selectively dysregulates the expression of cardiac-specific genes by depleting levels of cardiac-specific transcription factors and of co-activators. We will investigate the central roles of Mef2C acetylation by p300 and PCAF in cardiac specific gene expression and the response to Dox. Because depleted levels of acetylated histones H4, we will study whether Dox toxicity is due to modification of chromatin acetylation as a result of the loss of p300 and/or PCAF histone acetyltransferase activities. We will also investigate whether the modification of chromatin acetylation is due to a recruitment of histones deacetylases. Because Dox inhibits the expression of calcium/calmodulin-dependent protein kinase (CaMK) II(B, the predominant isoform of CaMK in heart muscle, both in cardiomyocytes in culture and also in rats chronically treated with the drug, we will investigate the role of the kinase in the cardiomyopathy induced by the agent. These studies will help define the mechanisms of cardiac side effects of a widely used chemotherapeutic agent and potentially lead to protective approaches.
