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A small-molecule allosteric inhibitor of BAX protects against doxorubicin-induced cardiomyopathy.

ABSTRACT: Doxorubicin remains an essential component of many cancer regimens, but its use is limited by lethal cardiomyopathy, which has been difficult to target, owing to pleiotropic mechanisms leading to apoptotic and necrotic cardiac cell death. Here we show that BAX is rate-limiting in doxorubicin-induced cardiomyopathy and identify a small-molecule BAX inhibitor that blocks both apoptosis and necrosis to prevent this syndrome. By allosterically inhibiting BAX conformational activation, this compound blocks BAX translocation to mitochondria, thereby abrogating both forms of cell death. When co-administered with doxorubicin, this BAX inhibitor prevents cardiomyopathy in zebrafish and mice. Notably, cardioprotection does not compromise the efficacy of doxorubicin in reducing leukemia or breast cancer burden in vivo, primarily due to increased priming of mitochondrial death mechanisms and higher BAX levels in cancer cells. This study identifies BAX as an actionable target for doxorubicin-induced cardiomyopathy and provides a prototype small-molecule therapeutic.

SUBMITTER: Amgalan D

PROVIDER: S-EPMC7413180 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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A small-molecule allosteric inhibitor of BAX protects against doxorubicin-induced cardiomyopathy.

Amgalan Dulguun D Garner Thomas P TP Pekson Ryan R Jia Xiaotong F XF Yanamandala Mounica M Paulino Victor V Liang Felix G FG Corbalan J Jose JJ Lee Jaehoon J Chen Yun Y Karagiannis George S GS Sanchez Luis Rivera LR Liang Huizhi H Narayanagari Swathi-Rao SR Mitchell Kelly K Lopez Andrea A Margulets Victoria V Scarlata Marco M Santulli Gaetano G Asnani Aarti A Peterson Randall T RT Hazan Rachel B RB Condeelis John S JS Oktay Maja H MH Steidl Ulrich U Kirshenbaum Lorrie A LA Gavathiotis Evripidis E Kitsis Richard N RN

Nature cancer 20200302 3

Doxorubicin remains an essential component of many cancer regimens, but its use is limited by lethal cardiomyopathy, which has been difficult to target, owing to pleiotropic mechanisms leading to apoptotic and necrotic cardiac cell death. Here we show that BAX is rate-limiting in doxorubicin-induced cardiomyopathy and identify a small-molecule BAX inhibitor that blocks both apoptosis and necrosis to prevent this syndrome. By allosterically inhibiting BAX conformational activation, this compound ...[more]

PMID: 32776015

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Project description:The aim of this study was to test the hypothesis that long-term dietary nitrate supplementation protects against doxorubicin-induced cardiomyopathy by improving ventricular function and reducing mitochondrial respiratory chain damage.Doxorubicin is a powerful anthracycline antibiotic used to treat divergent human neoplasms. Its clinical use is limited because of severe cardiotoxic side effects. Dietary nitrate and nitrite are essential nutrients for maintenance of steady-state tissue levels of nitric oxide and may play a therapeutic role in diseases associated with nitric oxide insufficiency or dysregulation. Dietary nitrate and nitrite supplementation alleviates myocardial injury caused by ischemia-reperfusion and cardiac arrest-resuscitation.Adult male CF-1 mice were given a single dose of doxorubicin (15 mg/kg intraperitoneally), and left ventricular contractile function was assessed 5 days later using both echocardiography and pressure-volume Millar catheterization. A nitrate supplementation regimen (1 g/l sodium nitrate in drinking water) was started 7 days before doxorubicin injection and continued thereafter. Cardiomyocyte necrosis and apoptosis, tissue lipid peroxidation, and plasma nitrate and nitrite levels were assessed. In addition, mitochondrial complex I activity, oxidative phosphorylation capacity, and hydrogen peroxide generation were determined in parallel experiments.Doxorubicin caused impairment of ventricular contractility and cell death, which were significantly reduced by nitrate supplementation (p < 0.05). These cardioprotective effects were associated with a significant decrease in tissue lipid peroxidation. Nitrate supplementation significantly preserved mitochondrial complex I activity and oxidative phosphorylation and attenuated hydrogen peroxide generation after doxorubicin treatment.Long-term oral intake of inorganic nitrate attenuates doxorubicin-induced ventricular dysfunction, cell death, oxidative stress, and mitochondrial respiratory chain damage. Nitrate could be a promising therapeutic agent against doxorubicin-induced cardiotoxicity.

Dataset Information

A small-molecule allosteric inhibitor of BAX protects against doxorubicin-induced cardiomyopathy.

Publications

A small-molecule allosteric inhibitor of BAX protects against doxorubicin-induced cardiomyopathy.

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