A metabolism-specific drug-repurposing screen reveals itraconazole as a potent OXPHOS inhibitor in acute myeloid leukemia - PubMed
5 hours ago
- #acute myeloid leukemia
- #OXPHOS inhibitor
- #itraconazole
- Targeting mitochondrial oxidative phosphorylation (OXPHOS) enhances chemotherapy effects and overcomes treatment resistance in AML.
- A high-throughput drug-repurposing screen identified itraconazole, an FDA-approved antifungal, as a potent OXPHOS inhibitor in AML cells.
- Itraconazole inhibits OXPHOS by interfering with electron transport chain complex I activity and tricarboxylic acid cycle function.
- CYP51A1, part of the cytochrome P450 family, is involved in mitochondrial respiration and complex I activity in AML cells.
- Over-expression of yeast NADH dehydrogenase-1 (NDI1) restored mitochondrial NADH oxidation and complex I activity after itraconazole treatment.
- Itraconazole, combined with cytarabine, effectively targets therapy-resistant leukemic stem cells (LSCs) in patient-derived and pre-clinical models.
- The study highlights the potential for repurposing itraconazole as a safe and effective therapeutic option for AML LSC eradication.