Pharmacological reduction of mitochondrial iron triggers a non-canonical BAX/BAK dependent cell death
Journal Title
Cancer Discovery
Publication Type
epub ahead of print
Abstract
Cancer cell metabolism is increasingly recognised 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 (AM5) 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 non-redundant pathways, we find that ironomycin exhibits marked in vitro and in vivo synergy with venetoclax and overcomes venetoclax resistance in primary patient samples.
Publisher
AACR
WEHI Research Division(s)
Blood Cells And Blood Cancer
PubMed ID
34862195
Open Access at Publisher's Site
https://doi.org/10.1158/2159-8290.CD-21-0522
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2021-12-07 12:04:01
Last Modified: 2021-12-07 12:21:01
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