Visnagin protects against doxorubicin-induced cardiomyopathy through modulation of mitochondrial malate dehydrogenase.
Visnagin protects against doxorubicin-induced cardiomyopathy through modulation of mitochondrial malate dehydrogenase.
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DOI：
10.1126/scitranslmed.3010189
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发表时间：
2014-12-10
影响因子：
17.1
通讯作者：
Peterson RT
中科院分区：
文献类型：
--
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
阿霉素是一种高效的抗癌化疗药物，但其心脏毒性限制了其使用。为了开发一种药物，防止心脏毒性的阿霉素，同时保持其抗肿瘤的效力，我们建立了一个阿霉素诱导的心肌病模型，在斑马鱼，重现心肌细胞凋亡和收缩力下降观察到的患者。使用该模型，我们筛选了3000种化合物，发现visnagin（维斯）和二苯基脲（DPU）可以挽救斑马鱼中阿霉素治疗引起的心脏性能和循环缺陷。维斯和DPU减少阿霉素诱导的心肌细胞凋亡，并在体内斑马鱼和小鼠心脏。此外，维斯治疗改善了阿霉素治疗小鼠的心肌收缩力。重要的是，维斯和DPU不会降低多柔比星在几种培养肿瘤系或斑马鱼和小鼠异种移植模型中的化疗功效。使用亲和层析，我们发现维斯结合线粒体苹果酸脱氢酶（MDH 2），在三羧酸循环的关键酶之一。与维斯一样，用MDH 2抑制剂甲苯咪唑、甲状腺素和碘治疗可以预防阿霉素的心脏毒性，用苹果酸本身治疗也是如此，这表明MDH 2活性的调节是维斯的心脏保护作用的原因。总之，这项研究确定了维斯和DPU作为有效的心脏保护化合物，并暗示MDH 2作为以前未描述的多柔比星诱导的心肌病的药物靶点。
Doxorubicin is a highly effective anti-cancer chemotherapy agent, but its usage is limited by its cardiotoxicity. To develop a drug that prevents the cardiac toxicity of doxorubicin while preserving its anti-tumor potency, we established a doxorubicin-induced cardiomyopathy model in zebrafish that recapitulated the cardiomyocyte apoptosis and contractility decline observed in patients. Using this model, we screened 3000 compounds and discovered that visnagin (VIS) and diphenylurea (DPU) rescue cardiac performance and circulatory defects caused by doxorubicin treatment in zebrafish. VIS and DPU reduced doxorubicin-induced apoptosis in cultured cardiomyocytes and in vivo in zebrafish and mouse hearts. Furthermore, VIS treatment improved cardiac contractility in doxorubicin-treated mice. Importantly, VIS and DPU caused no reduction in the chemotherapeutic efficacy of doxorubicin in several cultured tumor lines or in zebrafish and mouse xenograft models. Using affinity chromatography, we discovered that VIS binds to mitochondrial malate dehydrogenase (MDH2), one of the key enzymes in the tricarboxylic acid cycle. As with VIS, treatment with the MDH2 inhibitors mebendazole, thyroxine, and iodine prevented doxorubicin cardiotoxicity, as did treatment with malate itself, suggesting that modulation of MDH2 activity is responsible for VIS’s cardioprotective effects. Taken together, this study identified VIS and DPU as potent cardioprotective compounds and implicates MDH2 as a previously undescribed, druggable target for doxorubicin-induced cardiomyopathy.
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影响因子：
9.8
作者：
Haldi, Maryann;Ton, Christopher;McGrath, Patricia
通讯作者：
McGrath, Patricia
影响因子：
4.6
作者：
Le, Xiuning;Pugach, Emily K.;Zon, Leonard I.
通讯作者：
Zon, Leonard I.
影响因子：
20.1
作者：
Ky B;Vejpongsa P;Yeh ET;Force T;Moslehi JJ
通讯作者：
Moslehi JJ
影响因子：
11.2
作者：
Lyu, Yi Lisa;Kerrigan, John E.;Liu, Leroy F.
通讯作者：
Liu, Leroy F.
影响因子：
3.2
作者：
Hasinoff, Brian B.;Herman, Eugene H.
通讯作者：
Herman, Eugene H.