Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands;
Department of Head and Neck Oncology and Surgery, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
Proc Natl Acad Sci U S A. 2020 Jun 30;117(26):15182-15192. doi: 10.1073/pnas.1922072117. Epub 2020 Jun 17.
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.
蒽环类药物阿霉素（Doxo）及其类似物柔红霉素（Daun）、表柔比星（Epi）和伊达比星（Ida）已成为近五十年抗癌治疗的基石。然而，其临床应用受到严重副作用的限制，尤其是剂量依赖性的不可逆性心脏毒性。蒽环类药物的其他有害副作用包括治疗相关的恶性肿瘤和不育症。目前尚不清楚这些副作用是否与化疗疗效相关。Doxo、Daun、Epi 和 Ida 执行两种细胞活动：DNA 损伤，导致拓扑异构酶 II（Topo II）中毒后的双链断裂（DSBs），以及染色质损伤，通过在基因组中的选定部位驱逐组蛋白介导。在这里，我们报告蒽环类药物诱导的心脏毒性需要这两种细胞活动的结合。具有其中一种活性的 Topo II 毒物未能在小鼠和人心肌微组织中引起心脏毒性，如阿克拉霉素（Acla）和依托泊苷（Etop）所见。此外，我们表明 Doxo 可以通过化学分离这两种活性来解毒。不会引起 DSBs 但会引起染色质损伤的蒽环类药物变体在细胞系、小鼠和人类急性髓系白血病患者中保持相似的抗癌效力，这表明染色质损伤构成了蒽环类药物的主要细胞毒性机制。由于这些蒽环类药物没有心脏毒性和治疗相关的肿瘤，我们因此将副作用与抗癌疗效分开。这些结果表明，主要通过染色质损伤起作用的蒽环类药物变体可能允许延长癌症患者的治疗时间，并提高癌症幸存者的生活质量。
