Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death - Archive ouverte HAL
Article Dans Une Revue Cancer Discovery Année : 2022

Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death

Andrew Guirguis
Fiona Brown
Caitlin Rowe
James Kuzich
Kah Lok Chan
Brian Liddicoat
Sarah-Jane Dawson
Andrew Cox
Kristin Brown
Kate Mcarthur
Mark Dawson

Résumé

Abstract Cancer cell metabolism is increasingly recognized as providing an exciting therapeutic opportunity. However, a drug that directly couples targeting of a metabolic dependency with the induction of cell death in cancer cells has largely remained elusive. Here we report that the drug-like small-molecule ironomycin reduces the mitochondrial iron load, resulting in the potent disruption of mitochondrial metabolism. Ironomycin promotes the recruitment and activation of BAX/BAK, but the resulting mitochondrial outer membrane permeabilization (MOMP) does not lead to potent activation of the apoptotic caspases, nor is the ensuing cell death prevented by inhibiting the previously established pathways of programmed cell death. Consistent with the fact that ironomycin and BH3 mimetics induce MOMP through independent nonredundant pathways, we find that ironomycin exhibits marked in vitro and in vivo synergy with venetoclax and overcomes venetoclax resistance in primary patient samples. Significance: Ironomycin couples targeting of cellular metabolism with cell death by reducing mitochondrial iron, resulting in the alteration of mitochondrial metabolism and the activation of BAX/BAK. Ironomycin induces MOMP through a different mechanism to BH3 mimetics, and consequently combination therapy has marked synergy in cancers such as acute myeloid leukemia. This article is highlighted in the In This Issue feature, p. 587
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hal-03821713 , version 1 (09-11-2023)

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Sylvain Garciaz, Andrew Guirguis, Sebastian Müller, Fiona Brown, Yih-Chih Chan, et al.. Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death. Cancer Discovery, 2022, 12 (3), pp.774-791. ⟨10.1158/2159-8290.CD-21-0522⟩. ⟨hal-03821713⟩
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