The Chinese University of Hong Kong (CUHK), Hong Kong
Abstract: Doxorubicin (DOX) can effectively suppress cancer but cause serious damage to heart tissues. Dexrazoxane (DRZ) is the only FDA-approved treatment for DOX-induced cardiotoxicity but has been shown to interfere with the antitumor effects of DOX. Our previous work has shown that ICG-001, an inhibitor of β-catenin/CBP, can alleviate toxicity, but the latter has questionable translational potential. In this project, we investigate the potential of PRI-724, an analogue of ICG-001 which has been shown to well-tolerated in patients, to inhibit DOX-induced cardiotoxicity. Using patients-derived iPSC-CM and mouse models, we showed that PRI-724 alleviated CM damage induced by DOX in vitro and in vivo and its cardioprotective effects were comparable to the conventional treatment by DRZ. PRI-724 also showed cancer suppressive effects while DRZ did not. We concluded that PRI-724 is effective against DOX-induced cardiotoxicity in vitro and in vivo, and our results support future clinical studies of this compound to improve the safety and efficacy of DOX treatment to improve patient outcome.
