The anthracycline doxorubicin (Doxo) and its analogs daunorubicin (Daun), epirubicin (Epi), and idarubicin (Ida) have been cornerstones of anticancer therapy for nearly five decades. However, their clinical application is limited by severe side effects, especially dose-dependent irreversible cardiotoxicity. Other detrimental side effects of anthracyclines include therapy-related malignancies and infertility. It is unclear whether these side effects are coupled to the chemotherapeutic efficacy. Doxo, Daun, Epi, and Ida execute two cellular activities: DNA damage, causing double-strand breaks (DSBs) following poisoning of topoisomerase II (Topo II), and chromatin damage, mediated through histone eviction at selected sites in the genome. Here we report that anthracycline-induced cardiotoxicity requires the combination of both cellular activities. Topo II poisons with either one of the activities fail to induce cardiotoxicity in mice and human cardiac microtissues, as observed for aclarubicin (Acla) and etoposide (Etop). Further, we show that Doxo can be detoxified by chemically separating these two activities. Anthracycline variants that induce chromatin damage without causing DSBs maintain similar anticancer potency in cell lines, mice, and human acute myeloid leukemia patients, implying that chromatin damage constitutes a major cytotoxic mechanism of anthracyclines. With these anthracyclines abstained from cardiotoxicity and therapy-related tumors, we thus uncoupled the side effects from anticancer efficacy. These results suggest that anthracycline variants acting primarily via chromatin damage may allow prolonged treatment of cancer patients and will improve the quality of life of cancer survivors.

近五十年来，蒽环霉素阿霉素（Doxo）及其类似物柔红霉素（Daun），表柔比星（Epi）和伊达柔比星（Ida）一直是抗癌治疗的基石。然而，它们的临床应用受到严重副作用的限制，特别是剂量依赖性不可逆的心脏毒性。蒽环类药物的其他有害副作用包括与治疗有关的恶性肿瘤和不育症。尚不清楚这些副作用是否与化疗功效相关。Doxo，Daun，Epi和Ida执行两种细胞活动：DNA损伤，在拓扑异构酶II（Topo II）中毒后引起双链断裂（DSB），以及染色质损伤，通过组蛋白在基因组中选定位点的驱逐而介导。在这里我们报道蒽环类药物引起的心脏毒性需要两种细胞活性的结合。如对阿克拉霉素（Acla）和依托泊苷（Etop）所观察到的那样，具有任何一种活性的Topo II毒药均无法在小鼠和人的心脏微组织中诱发心脏毒性。此外，我们表明Doxo可以通过化学分离这两种活性而被解毒。在不引起DSB的情况下诱导染色质破坏的蒽环类药物变体在细胞系，小鼠和人类急性髓细胞性白血病患者中维持相似的抗癌效力，这意味着染色质破坏是蒽环类药物的主要细胞毒性机制。由于这些蒽环类药物因心脏毒性和与治疗有关的肿瘤而无法使用，因此，我们将抗癌药的副作用与不良反应联系在一起。