Highly potent visnagin derivatives inhibit Cyp1 and prevent doxorubicin cardiotoxicity
Highly potent visnagin derivatives inhibit Cyp1 and prevent doxorubicin cardiotoxicity
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DOI：
10.1172/jci.insight.96753
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发表时间：
2018-01-11
期刊：
影响因子：
8
通讯作者：
Peterson, Randall T.
中科院分区：
文献类型：
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作者：
Asnani, Aarti;Zheng, Bahoui;Peterson, Randall T.
阿霉素等蒽环类药物是用于治疗许多常见恶性肿瘤的高效化疗药物。然而，它们的使用受到心脏毒性的限制。我们之前发现维那金可以防止心脏细胞而非肿瘤细胞中的阿霉素毒性。在这项研究中，我们寻求开发更有效的维斯纳金类似物，以便使用这些类似物作为工具来阐明维斯纳金介导的心脏保护机制。在阿霉素心肌病斑马鱼模型中进行结构-活性关系研究。将 5-羰基移动到 7 位并添加短酯侧链导致了 visnagin 类似物的开发，其在斑马鱼中的效力增加了 1,000 倍，在小鼠中的效力增加了 250 倍。利用蛋白质组学，我们发现阿霉素会强烈诱导细胞色素 P450 家族 1 (CYP1)，而维斯那金及其有效类似物 23 可减轻这种诱导作用。使用结构不同的 CYP1 抑制剂治疗以及敲低 CYP1A，可以预防斑马鱼中的阿霉素心肌病。有效的心脏保护剂的鉴定可能有助于为接受心脏毒性化疗的患者开发新的治疗策略。此外，这些研究支持 CYP1 是阿霉素心脏毒性的重要贡献者的观点，并表明调节该途径可能在临床环境中有益。
Anthracyclines such as doxorubicin are highly effective chemotherapy agents used to treat many common malignancies. However, their use is limited by cardiotoxicity. We previously identified visnagin as protecting against doxorubicin toxicity in cardiac but not tumor cells. In this study, we sought to develop more potent visnagin analogs in order to use these analogs as tools to clarify the mechanisms of visnagin-mediated cardioprotection. Structure-activity relationship studies were performed in a zebrafish model of doxorubicin cardiomyopathy. Movement of the 5-carbonyl to the 7 position and addition of short ester side chains led to development of visnagin analogs with 1,000-fold increased potency in zebrafish and 250-fold increased potency in mice. Using proteomics, we discovered that doxorubicin caused robust induction of Cytochrome P450 family 1 (CYP1) that was mitigated by visnagin and its potent analog 23. Treatment with structurally divergent CYP1 inhibitors, as well as knockdown of CYP1A, prevented doxorubicin cardiomyopathy in zebrafish. The identification of potent cardioprotective agents may facilitate the development of new therapeutic strategies for patients receiving cardiotoxic chemotherapy. Moreover, these studies support the idea that CYP1 is an important contributor to doxorubicin cardiotoxicity and suggest that modulation of this pathway could be beneficial in the clinical setting.