| Literature DB >> 32776015 |
Dulguun Amgalan1,2,3, Thomas P Garner3,4, Ryan Pekson1,3, Xiaotong F Jia2,3, Mounica Yanamandala1,3,5, Victor Paulino1,3, Felix G Liang2,3, J Jose Corbalan1,3, Jaehoon Lee1,3, Yun Chen1,2,3, George S Karagiannis6,7,8, Luis Rivera Sanchez6,9, Huizhi Liang10, Swathi-Rao Narayanagari2,11, Kelly Mitchell2, Andrea Lopez3,4, Victoria Margulets12,13, Marco Scarlata1,3, Gaetano Santulli1,3,14, Aarti Asnani15,16, Randall T Peterson15,17, Rachel B Hazan10,11, John S Condeelis6,7,8,9,11, Maja H Oktay6,7,8,10,11, Ulrich Steidl1,2,11, Lorrie A Kirshenbaum12,13, Evripidis Gavathiotis18,19,20,21, Richard N Kitsis22,23,24,25.
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.Entities:
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Year: 2020 PMID： 32776015 PMCID： PMC7413180 DOI： 10.1038/s43018-020-0039-1
Source DB: PubMed Journal: Nat Cancer ISSN： 2662-1347