Abstract Body (Do not enter title and authors here): Introduction: Doxorubicin (DOX) is widely used in cancer treatment but may cause mitochondrial damage and cardiotoxicity. Dexrazoxane is the only clinically approved intervention for DOX-induced cardiotoxicity (DCT); however, it may reduce DOX's anti-cancer effectiveness. The discovery of new drugs is hampered by the lack of appropriate human models and the challenge of balancing cardioprotection with cancer management.
Aims: We aim to establish a clinically relevant model of DCT and identify novel treatment.
Methods: We previously identified CD36 as a surface marker of CM maturation. Human pluripotent stem cell derived (hPSC)-cardiomyocytes (CMs) with high CD36 (CD36^hi CM) have more mitochondria. They also recapitulate the protective effects of dexrazoxane against DCT, unlike immature, conventional hiPSC-CM cultures. Here, we established a clinically relevant model of DCT using patient-derived hiPSC-CD36hi CMs. Using this model, we performed a targeted screen to identify compounds that can supress DCT. Selected candidates were further tested for their effects on a panel of cancer cells. Cardioprotective effects were then validated in mouse in vivo models.
Results: Patient-derived CD36^hi hiPSC-CMs had more mitochondria and better mitochondrial function relative to CD36^lo CMs, and recapitulated the protective effects of dexrazoxane against DCT. Using this model, we identified drug candidates that can protect the mitochondria and increase CM viability. Further screening revealed a subset of candidates that do not affect or even suppress the viability of cancer cells. Echocardiography and histopathological examinations confirmed cardioprotection in vivo.
Conclusion: Patient-derived CD36^hi CMs is critical for the identification of new treatment against DCT. Using this and an in vivo model, we identified candidates that suppress DCT without protecting or even suppress cancer.