A small-molecule allosteric inhibitor of BAX protects against doxorubicin-induced cardiomyopathy.
Journal
Nature cancer
ISSN: 2662-1347
Titre abrégé: Nat Cancer
Pays: England
ID NLM: 101761119
Informations de publication
Date de publication:
03 2020
03 2020
Historique:
entrez:
11
8
2020
pubmed:
11
8
2020
medline:
11
8
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32776015
doi: 10.1038/s43018-020-0039-1
pmc: PMC7413180
mid: NIHMS1611835
pii: 10.1038/s43018-020-0039-1
doi:
Substances chimiques
bcl-2-Associated X Protein
0
Doxorubicin
80168379AG
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Pagination
315-328Subventions
Organisme : NCI NIH HHS
ID : P01 CA100324
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL138475
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL130861
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL128071
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA178394
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA200561
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL144456
Pays : United States
Organisme : FIC NIH HHS
ID : D43 TW010463
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA170911
Pays : United States
Déclaration de conflit d'intérêts
Competing interests R.N.K., E.G., D.A., T.P.G. and L.A.K. are inventors on a patent application PCT/US2018/021644 submitted by Albert Einstein College of Medicine that covers compounds, compositions and methods for BAX inhibition for the treatment of diseases and disorders.
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