Anthracycline antitumor agents, such as doxorubicin (DOX), are effective in the treatment of solid tumors and hematological malignancies, but anthracycline-induced cardiotoxicity (AIC) limits their application as chemotherapeutics. Dexrazoxane (DEX) has been adopted to prevent AIC. Using a chronic AIC mouse model, we demonstrated that DEX is insufficient to reverse DOX-induced cardiotoxicity. Although therapies targeting autophagy have been explored to prevent AIC, but whether novel autophagy inhibitors could alleviate or prevent AIC in clinically relevant models needs further investigation. Here, we show that genetic ablation of Atg7, a key regulator in the early phase of autophagy, protected mice against AIC. We further demonstrated that SAR405, a novel autophagy inhibitor, attenuated DOX-induced cytotoxicity. Intriguingly, the combination of DEX and SAR405 protected cells against DOX-induced cardiotoxicity in vivo. Using the cardiomyocyte cell lines AC16 and H9c2, we determined that autophagy was initiated during AIC. Our results suggest that inhibition of autophagy at its early phase with SAR405 combined with DEX represents an effective therapeutic strategy to prevent AIC.

蒽环类抗肿瘤药物，如阿霉素（DOX），可有效治疗实体瘤和血液恶性肿瘤，但蒽环类药物引起的心脏毒性（AIC）限制了其作为化疗药物的应用。右雷佐生 (DEX) 已被用于预防 AIC。使用慢性 AIC 小鼠模型，我们证明 DEX 不足以逆转 DOX 诱导的心脏毒性。尽管已经探索了针对自噬的疗法来预防 AIC，但新型自噬抑制剂是否可以在临床相关模型中减轻或预防 AIC 需要进一步研究。在这里，我们证明 Atg7（自噬早期的关键调节因子）的基因消除可以保护小鼠免受 AIC 的侵害。我们进一步证明，新型自噬抑制剂 SAR405 可以减弱 DOX 诱导的细胞毒性。有趣的是，DEX 和 SAR405 的组合可以保护细胞免受 DOX 诱导的体内心脏毒性。使用心肌细胞系 AC16 和 H9c2，我们确定自噬是在 AIC 期间启动的。我们的结果表明，SAR405 联合 DEX 在早期阶段抑制自噬是预防 AIC 的有效治疗策略。