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Biological and metabolic effects of IACS-010759, an OxPhos inhibitor, on chronic lymphocytic leukemia cells

Blood cells from patients with chronic lymphocytic leukemia (CLL) are replicationally quiescent but transcriptionally, translationally, and metabolically active. Recently, we demonstrated that oxidative phosphorylation (OxPhos) is a predominant pathway in CLL for energy production and is further aug...

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Autores principales: Vangapandu, Hima V., Alston, Brandon, Morse, Joshua, Ayres, Mary L., Wierda, William G., Keating, Michael J., Marszalek, Joseph R., Gandhi, Varsha
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5982765/
https://www.ncbi.nlm.nih.gov/pubmed/29861847
http://dx.doi.org/10.18632/oncotarget.25166
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author Vangapandu, Hima V.
Alston, Brandon
Morse, Joshua
Ayres, Mary L.
Wierda, William G.
Keating, Michael J.
Marszalek, Joseph R.
Gandhi, Varsha
author_facet Vangapandu, Hima V.
Alston, Brandon
Morse, Joshua
Ayres, Mary L.
Wierda, William G.
Keating, Michael J.
Marszalek, Joseph R.
Gandhi, Varsha
author_sort Vangapandu, Hima V.
collection PubMed
description Blood cells from patients with chronic lymphocytic leukemia (CLL) are replicationally quiescent but transcriptionally, translationally, and metabolically active. Recently, we demonstrated that oxidative phosphorylation (OxPhos) is a predominant pathway in CLL for energy production and is further augmented in the presence of the stromal microenvironment. Importantly, CLL cells from patients with poor prognostic markers showed increased OxPhos. From these data, we theorized that OxPhos can be targeted to treat CLL. IACS-010759, currently in clinical development, is a small-molecule, orally bioavailable OxPhos inhibitor that targets mitochondrial complex I. Treatment of primary CLL cells with IACS-010759 greatly inhibited OxPhos but caused only minor cell death at 24 and 48 h. In the presence of stroma, the drug successfully inhibited OxPhos and diminished intracellular ribonucleotide pools. However, glycolysis and glucose uptake were induced as compensatory mechanisms. To mitigate the upregulated glycolytic flux, we used 2-deoxy-D-glucose in combination with IACS-010759. This combination reduced both OxPhos and glycolysis and induced cell death. Consistent with these data, low-glucose culture conditions sensitized CLL cells to IACS-010759. Collectively, these data suggest that CLL cells adapt to use a different metabolic pathway when OxPhos is inhibited and that targeting both OxPhos and glycolysis pathways is necessary for biological effect.
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spelling pubmed-59827652018-06-01 Biological and metabolic effects of IACS-010759, an OxPhos inhibitor, on chronic lymphocytic leukemia cells Vangapandu, Hima V. Alston, Brandon Morse, Joshua Ayres, Mary L. Wierda, William G. Keating, Michael J. Marszalek, Joseph R. Gandhi, Varsha Oncotarget Research Paper Blood cells from patients with chronic lymphocytic leukemia (CLL) are replicationally quiescent but transcriptionally, translationally, and metabolically active. Recently, we demonstrated that oxidative phosphorylation (OxPhos) is a predominant pathway in CLL for energy production and is further augmented in the presence of the stromal microenvironment. Importantly, CLL cells from patients with poor prognostic markers showed increased OxPhos. From these data, we theorized that OxPhos can be targeted to treat CLL. IACS-010759, currently in clinical development, is a small-molecule, orally bioavailable OxPhos inhibitor that targets mitochondrial complex I. Treatment of primary CLL cells with IACS-010759 greatly inhibited OxPhos but caused only minor cell death at 24 and 48 h. In the presence of stroma, the drug successfully inhibited OxPhos and diminished intracellular ribonucleotide pools. However, glycolysis and glucose uptake were induced as compensatory mechanisms. To mitigate the upregulated glycolytic flux, we used 2-deoxy-D-glucose in combination with IACS-010759. This combination reduced both OxPhos and glycolysis and induced cell death. Consistent with these data, low-glucose culture conditions sensitized CLL cells to IACS-010759. Collectively, these data suggest that CLL cells adapt to use a different metabolic pathway when OxPhos is inhibited and that targeting both OxPhos and glycolysis pathways is necessary for biological effect. Impact Journals LLC 2018-05-18 /pmc/articles/PMC5982765/ /pubmed/29861847 http://dx.doi.org/10.18632/oncotarget.25166 Text en Copyright: © 2018 Vangapandu et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (http://creativecommons.org/licenses/by/3.0/) (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Vangapandu, Hima V.
Alston, Brandon
Morse, Joshua
Ayres, Mary L.
Wierda, William G.
Keating, Michael J.
Marszalek, Joseph R.
Gandhi, Varsha
Biological and metabolic effects of IACS-010759, an OxPhos inhibitor, on chronic lymphocytic leukemia cells
title Biological and metabolic effects of IACS-010759, an OxPhos inhibitor, on chronic lymphocytic leukemia cells
title_full Biological and metabolic effects of IACS-010759, an OxPhos inhibitor, on chronic lymphocytic leukemia cells
title_fullStr Biological and metabolic effects of IACS-010759, an OxPhos inhibitor, on chronic lymphocytic leukemia cells
title_full_unstemmed Biological and metabolic effects of IACS-010759, an OxPhos inhibitor, on chronic lymphocytic leukemia cells
title_short Biological and metabolic effects of IACS-010759, an OxPhos inhibitor, on chronic lymphocytic leukemia cells
title_sort biological and metabolic effects of iacs-010759, an oxphos inhibitor, on chronic lymphocytic leukemia cells
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5982765/
https://www.ncbi.nlm.nih.gov/pubmed/29861847
http://dx.doi.org/10.18632/oncotarget.25166
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