Programmed Cell Death 4 in Doxorubicin-Induced Cardiotoxicity - Project Summary Anthracyclines, such as doxorubicin (DOX), daunomycin, epirubicin, and idarubicin, are commonly used and highly successful anti-cancer drugs. Unfortunately, these medications often cause heart toxicity, which limits their effectiveness. Late onset anthracycline cardiotoxicity is refractory to standard treatments for heart failure. Childhood cancer survivors are particularly prone to anthracycline-induced heart failure. We have developed a juvenile mouse model exhibiting attributes consistent with both acute and chronic cardiotoxicities following DOX treatment. Programmed cell death 4 (PDCD4) is a gene that suppresses tumor growth via inducing cell apoptosis. Expression of PDCD4 is downregulated in many types of tumors. However, its function in the heart remains largely unknown. Our preliminary data demonstrated that PDCD4 may serve as a previously unrecognized cardioprotective molecule against DOX-induced cardiotoxicity. Specifically, our data showed that 1) PDCD4 expression is high in neonatal mouse hearts (i.e., postnatal day 1-7) and decreases by postnatal day 28; 2) DOX suppresses PDCD4 expression in cardiomyocytes; 3) overexpression of PDCD4 reduces, while knocking down of PDCD4 increases DOX- induced cardiomyocyte apoptosis; and 4) PDCD4 promotes the phosphorylation of STAT3. Collectively, these data suggest PDCD4 performs distinct roles in cancer cells compared to cardiomyocytes. Based on these findings, we aim to investigate the role of PDCD4 in DOX-induced cardiotoxicity in the juvenile mouse model. Our central hypothesis is that PDCD4 is a cardioprotective molecule against DOX-induced cardiotoxicity in vivo. Three specific aims are proposed to test the hypothesis. Aim 1 is to determine the role of PDCD4 in DOX-induced cardiotoxicity in juvenile mice. Aim 2 is to define the contribution of STAT3 in PDCD4-mediated cardioprotection. Aim 3 is to investigate whether increasing PDCD4 level through pharmacological interventions confers cardioprotection against DOX-induced cardiotoxicity. The experiments proposed in this application are based on a series of initial observations that have examined the molecular pathways contributing to DOX-induced cardiotoxicity in genetically modified mouse models. Ultimately, these studies could offer valuable insights for developing intervention strategies to reduce or reverse the cardiotoxic effects of anthracyclines, enabling more aggressive use of this drug and improving cancer treatment outcomes.
