PT  - JOURNAL ARTICLE
AU  - Liu, Yan
AU  - Asnani, Aarti
AU  - Zou, Lin
AU  - Bentley, Victoria L.
AU  - Yu, Min
AU  - Wang, You
AU  - Dellaire, Graham
AU  - Sarkar, Kumar S.
AU  - Dai, Matthew
AU  - Chen, Howard H.
AU  - Sosnovik, David E.
AU  - Shin, Jordan T.
AU  - Haber, Daniel A.
AU  - Berman, Jason N.
AU  - Chao, Wei
AU  - Peterson, Randall T.
TI  - Visnagin protects against doxorubicin-induced cardiomyopathy through modulation of mitochondrial malate dehydrogenase
AID  - 10.1126/scitranslmed.3010189
DP  - 2014 Dec 10
TA  - Science Translational Medicine
PG  - 266ra170--266ra170
VI  - 6
IP  - 266
4099  - http://stm.sciencemag.org/content/6/266/266ra170.short
4100  - http://stm.sciencemag.org/content/6/266/266ra170.full
AB  - Doxorubicin is a highly effective anticancer chemotherapy agent, but its use is limited by its cardiotoxicity. To develop a drug that prevents this toxicity, we established a doxorubicin-induced cardiomyopathy model in zebrafish that recapitulates the cardiomyocyte apoptosis and contractility decline observed in patients. Using this model, we screened 3000 compounds and found that visnagin (VIS) and diphenylurea (DPU) rescue the cardiac performance and circulatory defects caused by doxorubicin in zebrafish. VIS and DPU reduced doxorubicin-induced apoptosis in cultured cardiomyocytes and in vivo in zebrafish and mouse hearts. VIS treatment improved cardiac contractility in doxorubicin-treated mice. Further, VIS and DPU did not reduce the chemotherapeutic efficacy of doxorubicin in several cultured tumor lines or in zebrafish and mouse xenograft models. Using affinity chromatography, we found that VIS binds to mitochondrial malate dehydrogenase (MDH2), a key enzyme 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’ cardioprotective effects. Thus, VIS and DPU are potent cardioprotective compounds, and MDH2 is a previously undescribed, druggable target for doxorubicin-induced cardiomyopathy.