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

Garciaz, S; Guirguis, AA; Muller, S; Brown, FC; Chan, YC; Motazedian, A; Rowe, CL; Kuzich, JA; Chan, KL; Tran, K; Smith, L; MacPherson, L; Liddicoat, B; Lam, EYN; Caneque, T; Burr, ML; Litalien, V; Pomilio, G; Poplineau, M; Duprez, E; Dawson, SJ; Ramm, G; Cox, AG; Brown, KK; Huang, DCS; Wei, AH; McArthur, K; Rodriguez, R; Dawson, MA

Author(s): Garciaz, S; Guirguis, AA; Muller, S; Brown, FC; Chan, YC; Motazedian, A; Rowe, CL; Kuzich, JA; Chan, KL; Tran, K; Smith, L; MacPherson, L; Liddicoat, B; Lam, EYN; Caneque, T; Burr, ML; Litalien, V; Pomilio, G; Poplineau, M; Duprez, E; Dawson, SJ; Ramm, G; Cox, AG; Brown, KK; Huang, DCS; Wei, AH; McArthur, K; Rodriguez, R; Dawson, MA;
Details: Publication Year 2022-03-01,Volume 12,Issue #3,Page 774-791
Journal Title: Cancer Discovery
Publication Type: Research 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. 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.
Keywords: Apoptosis; Cell Death; Humans; *Iron/metabolism; Mitochondria/metabolism; *bcl-2 Homologous Antagonist-Killer Protein/metabolism; bcl-2-Associated X Protein/metabolism
Department(s): Laboratory Research; Haematology; Medical Oncology
PubMed ID: 34862195
Publisher's Version: https://doi.org/10.1158/2159-8290.CD-21-0522
Open Access at Publisher's Site: https://doi.org/10.1158/2159-8290.Cd-21-0522
Terms of Use/Rights Notice: Refer to copyright notice on published article.

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