Doxorubicin, a classic anthracycline, is widely used in modern cancer treatments, despite the advent of targeted therapy. However, a dose-dependent cardiotoxicity often limits its clinical use. Doxorubicin's cellular target is Topoisomerase II (Top2). Doxorubicin binds both DNA and Top2 to form the ternary Top2-doxorubicin-DNA cleavage complex, which triggers cell death. There are two Top2 enzymes, Top2a and Top2b. Top2a, a known marker of cell proliferation, is over-expressed in tumors but not detectable in quiescent tissues. Thus, Top2a is thought to be the molecular basis of doxorubicin's anti-tumor activity. On the other hand, doxorubicin is believed to cause dose-dependent cardiotoxicity through redox-cycling and generation of reactive oxygen species (ROS). Recently, we showed that cardiomyocyte-specific deletion of Top2b protected cardiomyocytes from doxorubicin-induced DNA double strand breaks and changes in transcriptome that are responsible for defective mitochondrial biogenesis and ROS formation. Furthermore, cardiomyocyte-specific deletion of Top2b protects mice from development of doxorubicin-induced progressive heart failure, suggesting that Top2b is the molecular basis of doxorubicin-induced cardiotoxicity. In this proposal, we will test the hypothesis that doxorubicin-induced cardiotoxicity is preventable by chemical induced-deletion of Top2b from cardiomyocytes. In preliminary studies, we showed that dexrazoxane induced degradation of Top2b through a proteasome- dependent mechanism. Thus, 8 hours after dexrazoxane administration, Top2b is completely eliminated from the heart. Remarkably, dexrazoxane does not affect Top2a stability in cancer cells. This insight prompt us to study the hypothesis that dexrazoxane-induced depletion of Top2b in the heart should be effective in preventing doxorubicin-induced cardiotoxicity, while preserving doxorubicin's tumor killing effect.
Three aims are proposed.
Specific Aim 1 : To determine whether dexrazoxane-induced degradation of Top2b in the heart prevents doxorubicin-induced cardiotoxicity, but preserves doxorubicin's tumoricidal activity.
Specific Aim 2 : To determine the mechanism of dexrazoxane-induced Top2b degradation.
Specific Aim 3 : To study the physiologic function of Top2b in cardiomyocytes. Successful completion of this proposal will provide critical insights into designing a new prevention strategy for doxorubicin-induced cardiotoxicity.
We propose to deplete Topoisomerase 2b (Top2b) from the heart to prevent doxorubicin-induced cardiotoxicity. In preliminary studies, we found that dexrazoxane induced degradation of Top2b through a SUMO and ubiquitin-dependent mechanism. We will conduct animal experiments to study whether pre- treatment with dexrazoxane will protect the heat from doxorubicin-induced cardiotoxicity; biochemical studies will also be carried out to elucidate the mechanism of dexrazoxane-induced Top2b degradation.
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