The Chinese University of Hong Kong (CUHK) Hong Kong, Hong Kong
Abstract: Doxorubicin (DOX) is effective against cancer, but can damage the mitochondria and cause DOX-induced cardiotoxicity (DCT). The identification of treatments is hampered by the lack of suitable human models and the need to balance cardioprotection and cancer control. Conventional human induced pluripotent stem cell derived-cardiomyocytes (hiPSC-CMs) have sparse mitochondria and do not recapitulate the cardioprotective effect of FDA-approved treatment, dexrazoxane. Here we established a patient-derived and mitochondria-rich hiPSC-CM model which was protected by dexrazoxane. Using these hiPSC-CMs and a mice model, we found that ICG-001, an inhibitor of Wnt/β-catenin signalling and dynamin-related protein 1 (DRP1), suppressed DCT in vitro and in vivo, similar to dexrazoxane. Unlike dexrazoxane, ICG-001 was cytotoxic to cancer cells. Mechanistically, ICG-001 inhibited DRP1 and protected the mitochondria in CMs, but repressed Wnt signalling and killed cancer cells. In summary, our mitochondria-rich, patient-derived, mitochondria-rich CM model is critical for the identification of new treatment against DCT. Using this and a mouse model, we showed that ICG-001 can protect the heart and suppress cancer by targeting different proteins/pathways, and is therefore potentially superior to conventional treatment with dexrazoxane.
