Abstract Mo018: Using a mitochondria-rich hiPSC-CM model to investigate doxorubicin-induced cardiotoxicity

Abstract

Doxorubicin (DOX) is commonly used to treat cancer but can induce severe cardiotoxicity by damaging the mitochondria. Dexrazoxane is clinically approved to protect against DOX-induced cardiotoxicity (DCT) but has been shown to reduce the anti-cancer efficacy of DOX and cause secondary neoplasm. Human induced pluripotent stem cell derived-cardiomyocyte (hiPSC-CMs) models have been used to study DOX-induced cardiotoxicity (DCT), but some do not correctly recapitulate patient response to dexrazoxane. This was previously attributed to the low mitochondrial abundance of these cells and is a hurdle against the identification of new therapeutics against DCT. Our aim is to use our patient-derived, mitochondria-rich hiPSC-CM model to identify compounds which can protect against DCT. We first checked that our hiPSC-CMs recapitulate the cardioprotective effects of dexrazoxane. Using this validated model, we showed that compound I1 suppressed both the mitochondrial and non-mitochondrial damage induced by DOX, at levels that are comparable to that of dexrazoxane. However, unlike dexrazoxane and contrary to its effects in CMs, compound I1 was cytotoxic to a panel of cancer cell lines. Mechanistic investigations indicated that the divergent effects of CMs vs cancer cells is due the ability of compound I1 to inhibit two distinct molecular targets in the two cell types. Lastly, we validated that compound I1 can protect the heart in an in vivo mouse model of DCT. In summary, compound I1 offers the dual benefits of cardioprotection and tumour suppression and is potentially superior to conventional treatment. Our results provide important proof of principle that a single compound can be used to simultaneously target both the heart and cancer via different targets/pathways to improve clinical outcome.