Neutral sphingomyelinase-2 as a mediator of Doxorubicin-induced cardiotoxicity

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ABSTRACT Doxorubicin (Dox) is a mainstay in the treatment of many cancers yet its utility is limited by cardiovascular toxicity. While multiple mechanisms underlying this cardiotoxicity have been proposed, strategies targeting these pathways have had marginal effects or interfere with anti-cancer effects of the drug. Such concerns have restricted the clinical use of dexrazoxane which is currently the only FDA-approved cardio-protective agent. As cancer survival rates improve and more patients are exposed to Dox, there is a critical need for new strategies to mitigate the cardiotoxicity without comprising its therapeutic efficacy. Bioactive sphingolipids (SLs), especially ceramide (Cer), are well-established mediators of the chemotherapy stress response across diverse cancers. While this increased interest in targeting SL metabolism to enhance chemotherapy responses, targeting SL metabolism to reduce chemotoxicities is largely unexplored. We recently identified the Cer-generating enzyme neutral sphingomyelinase-2 (nSMase2) as a primary Dox-regulated SL enzyme in breast cancer. Here, our preliminary studies begin to implicate nSMase2-derived Cer in the Dox-induced DNA damage response of cardiomyocytes (CMs) and show that in vivo loss of nSMase2 activity protects from the onset of Dox-induced cardiac dysfunction and damage. Crucially, nSMase2 appears to be dispensable for the in vitro and in vivo anti- cancer effects of Dox on breast cancer. Based on these data, the central hypothesis is that the nSMase2- ceramide pathway is essential for Dox-induced cardiotoxicity but dispensable for Dox-induced anti-cancer activity. We propose three specific aims: The first aim will establish Dox-induced activation of the nSMase2- Cer pathway in cardiac cells and tissues combining in vitro and in vivo approaches to establish nSMase2 induction in CMs as a major pathway of Dox-induced Cer generation in the heart. The second aim will define the role of the nSMase2-Cer pathway in mediating Dox-induced cardiotoxicity using in vitro and in vivo loss of function approaches to establish nSMase2 in CMs as a mediator of Dox-induced CM cell death and cardiac fibrosis. The third aim will establish the therapeutic potential of nSMase2 inhibitors as cardioprotective agents that do not interfere with the anti-cancer activity of Dox using syngeneic xenograft models of breast cancer to demonstrate the efficacy of nSMase2 inhibitors as cardioprotective agents that do not interfere with Dox reduction of tumor growth and metastasis. Overall, these studies will provide novel insight into the pathogenesis of Dox-induced cardiotoxicity and establish nSMase2 as a novel druggable target for cardioprotection. This will provide a rational basis for the development of nSMase2 inhibitors as novel cardioprotective agents.