Cyp1 Inhibition Prevents Doxorubicin-Induced Cardiomyopathy in a Zebrafish Heart-Failure Model.
Cyp1 Inhibition Prevents Doxorubicin-Induced Cardiomyopathy in a Zebrafish Heart-Failure Model.
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DOI：
10.1002/cbic.201900741
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发表时间：
2020-07-01
期刊：
影响因子：
--
通讯作者：
Peterson RT
中科院分区：
文献类型：
--
作者：
Lam PY;Kutchukian P;Anand R;Imbriglio J;Andrews C;Padilla H;Vohra A;Lane S;Parker DL Jr;Cornella Taracido I;Johns DG;Beerens M;MacRae CA;Caldwell JP;Sorota S;Asnani A;Peterson RT
阿霉素是一种高效的化疗药物，用于治疗许多常见的恶性肿瘤。然而，其使用受到心脏毒性的限制，并且累积剂量会呈指数增加心力衰竭的风险。为了确定新的心力衰竭治疗靶点，我们之前建立了阿霉素诱导的心肌病斑马鱼模型用于小分子筛选。使用该模型，我们之前在斑马鱼和小鼠模型中鉴定了几种可以预防阿霉素诱导的心脏毒性的小分子。在这项研究中，我们通过从专有的目标注释工具化合物集合中筛选 2,271 个小分子，扩大了对阿霉素心脏毒性的探索。我们发现了 120 种小分子可以预防阿霉素引起的心脏毒性，其中包括 7 种高效化合物。其中，所有七种均表现出对细胞色素 P450 家族 1 (CYP1) 的抑制活性。这些结果与我们之前的研究结果一致，即 CYP1 抑制剂 visnagin 也可以预防阿霉素诱导的心脏毒性。重要的是，cyp1a 的基因突变可以保护斑马鱼免受阿霉素诱导的心脏毒性表型。总之，这些结果提供了强有力的证据，表明 CYP1 是阿霉素诱导的心脏毒性的重要贡献者，并强调 CYP1 通路作为临床心脏保护的候选治疗靶点。阿霉素是一种有效的化疗药物，但其使用受到心脏毒性副作用的限制。使用阿霉素诱导的心肌病斑马鱼模型进行小分子筛选，CYP1 被确定为临床心脏保护的候选治疗靶点。
Doxorubicin is a highly effective chemotherapy agent used to treat many common malignancies. However, its use is limited by cardiotoxicity, and cumulative doses exponentially increase the risk of heart failure. To identify novel heart failure treatment targets, we previously established a zebrafish model of doxorubicin-induced cardiomyopathy for small molecule screening. Using this model, we previously identified several small molecules that prevent doxorubicin-induced cardiotoxicity both in zebrafish as well as in mouse models. In this study, we have expanded our exploration of doxorubicin cardiotoxicity by screening 2,271 small molecules from a proprietary, target-annotated tool compound collection. We found 120 small molecules that can prevent doxorubicin-induced cardiotoxicity, including seven highly-effective compounds. Of these, all seven exhibited inhibitory activity towards Cytochrome P450 family 1 (CYP1). These results are consistent with our previous findings in which visnagin, a CYP1 inhibitor, also prevented doxorubicin-induced cardiotoxicity. Importantly, genetic mutation of cyp1a protected zebrafish against doxorubicin-induced cardiotoxicity phenotypes. Together, these results provide strong evidence that CYP1 is an important contributor to doxorubicin-induced cardiotoxicity and highlight the CYP1 pathway as a candidate therapeutic target for clinical cardioprotection. Doxorubicin is a potent chemotherapy agent but its use is limited by cardiotoxic side effects. Using a zebrafish model of doxorubicin-induced cardiomyopathy for small molecule screening, CYP1 was identified as a candidate therapeutic target for clinical cardioprotection.
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影响因子：
3.4
作者：
McGowan JV;Chung R;Maulik A;Piotrowska I;Walker JM;Yellon DM
通讯作者：
Yellon DM
影响因子：
17.1
作者：
Liu Y;Asnani A;Zou L;Bentley VL;Yu M;Wang Y;Dellaire G;Sarkar KS;Dai M;Chen HH;Sosnovik DE;Shin JT;Haber DA;Berman JN;Chao W;Peterson RT
通讯作者：
Peterson RT
影响因子：
1.7
作者：
Zhang, Z;Schwartz, S;Miller, W
通讯作者：
Miller, W
影响因子：
8
作者：
Asnani, Aarti;Zheng, Bahoui;Peterson, Randall T.
通讯作者：
Peterson, Randall T.
影响因子：
2.5
作者：
Green, MD;Yang, XQ;King, CD
通讯作者：
King, CD