journal contribution
posted on 2023-04-04, 00:00 authored by Sylvain Garciaz, Andrew A. Guirguis, Sebastian Müller, Fiona C. Brown, Yih-Chih Chan, Ali Motazedian, Caitlin L. Rowe, James A. Kuzich, Kah Lok Chan, Kevin Tran, Lorey Smith, Laura MacPherson, Brian Liddicoat, Enid Y.N. Lam, Tatiana Cañeque, Marian L. Burr, Véronique Litalien, Giovanna Pomilio, Mathilde Poplineau, Estelle Duprez, Sarah-Jane Dawson, Georg Ramm, Andrew G. Cox, Kristin K. Brown, David C.S. Huang, Andrew H. Wei, Kate McArthur, Raphaël Rodriguez, Mark A. Dawson Supplementary Data from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Funding
NHMRC
Howard Hughes Medical Institute international research scholarship
European Union's Horizon 2020 research and innovation programme
NHMRC Investigator Grant
ARC Discovery Project Grant
NHMRC Project Grant
VCA Mid-Career Research Fellowship
Susan G. Komen Career Catalyst Research Grant
History
ARTICLE 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.
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
