A metabolism-specific drug-repurposing screen reveals itraconazole as a potent OXPHOS inhibitor in acute myeloid leukemia
Abstract
Abstract Targeting mitochondrial oxidative phosphorylation (OXPHOS) enhances the effects of standard chemotherapy and overcomes treatment resistance in preclinical models of acute myeloid leukemia (AML). So far, the few clinically available OXPHOS inhibitors have shown adverse effects or limited potency in clinical trials; therefore, the identification of safe and effective drugs that target mitochondrial metabolism in AML is critical. Here, we performed a high-throughput drug-repurposing screen designed to identify clinically applicable OXPHOS-specific inhibitors through nutrient sensing. We uncover itraconazole, a US Food and Drug Administration–approved antifungal compound, as a potent OXPHOS inhibitor in AML cells. Mechanistically, through stable isotope-assisted metabolomics and functional studies, we reveal that cytochrome P450 family 51 subfamily A member 1 (CYP51A1), which is part of the cytochrome P450 family and the prime target of azole antifungals, is involved in mitochondrial respiration and electron transport chain (ETC) complex I activity in AML cells. Critically, we demonstrate that itraconazole and related azole antifungals interfere with tricarboxylic acid cycle activity and inhibit OXPHOS through the inhibition of ETC complex I activity. Overexpression of yeast nicotinamide adenine dinucleotide (NADH) dehydrogenase-1 (NDI1) restored mitochondrial NADH oxidation and complex I activity following itraconazole treatment. Using patient-derived cells and preclinical xenograft models, we demonstrate that itraconazole targets therapy-resistant leukemic stem cells (LSCs) when used in combination with cytarabine, highlighting the repurposing potential for itraconazole as a clinically safe and effective therapeutic option for AML LSC eradication.
Article Details
Authors (21)
Ekaterini Himonas
1Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
Lucie de Beauchamp
1Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
Désirée Zerbst
1Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
Eudoxie Desmares-Romain
3Centre de Recherches en Cancérologie de Toulouse, Université de Toulouse, INSERM U1037, Centre National de la Recherche Scientifique U5077, Toulouse, France
Daniele Sarnello
1Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
Eric R. Kalkman
1Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
Kevin M. Rattigan
1Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
Daniel James
Engy Shokry
Mhairi Copland
7Paul O’Gorman Leukaemia Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
Emmanuel Griessinger
3Centre de Recherches en Cancérologie de Toulouse, Université de Toulouse, INSERM U1037, Centre National de la Recherche Scientifique U5077, Toulouse, France
Christian Récher
Véronique De Mas
3Centre de Recherches en Cancérologie de Toulouse, Université de Toulouse, INSERM U1037, Centre National de la Recherche Scientifique U5077, Toulouse, France
Francois Vergez
3Centre de Recherches en Cancérologie de Toulouse, Université de Toulouse, INSERM U1037, Centre National de la Recherche Scientifique U5077, Toulouse, France
David Sumpton
Aaron D. Schimmer
Mark D. Minden
Princess Margaret Cancer Centre, University Health Network
Eyal Gottlieb
Emma Shanks
6Cancer Research UK Scotland Institute, Glasgow, United Kingdom
Jean-Emmanuel Sarry
G. Vignir Helgason
1Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom