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Simultaneous targeting of glycolysis and oxidative phosphorylation as a therapeutic strategy to treat diffuse large B-cell lymphoma

BACKGROUND: We evaluated the therapeutic potential of combining the monocarboxylate transporter 1 (MCT1) inhibitor AZD3965 with the mitochondrial respiratory Complex I inhibitor IACS-010759, for the treatment of diffuse large B-cell lymphoma (DLBCL), a potential clinically actionable strategy to tar...

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Autores principales: Noble, Richard A., Thomas, Huw, Zhao, Yan, Herendi, Lili, Howarth, Rachel, Dragoni, Ilaria, Keun, Hector C., Vellano, Christopher P., Marszalek, Joseph R., Wedge, Stephen R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9428179/
https://www.ncbi.nlm.nih.gov/pubmed/35618788
http://dx.doi.org/10.1038/s41416-022-01848-w
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author Noble, Richard A.
Thomas, Huw
Zhao, Yan
Herendi, Lili
Howarth, Rachel
Dragoni, Ilaria
Keun, Hector C.
Vellano, Christopher P.
Marszalek, Joseph R.
Wedge, Stephen R.
author_facet Noble, Richard A.
Thomas, Huw
Zhao, Yan
Herendi, Lili
Howarth, Rachel
Dragoni, Ilaria
Keun, Hector C.
Vellano, Christopher P.
Marszalek, Joseph R.
Wedge, Stephen R.
author_sort Noble, Richard A.
collection PubMed
description BACKGROUND: We evaluated the therapeutic potential of combining the monocarboxylate transporter 1 (MCT1) inhibitor AZD3965 with the mitochondrial respiratory Complex I inhibitor IACS-010759, for the treatment of diffuse large B-cell lymphoma (DLBCL), a potential clinically actionable strategy to target tumour metabolism. METHODS: AZD3965 and IACS-010759 sensitivity were determined in DLBCL cell lines and tumour xenograft models. Lactate concentrations, oxygen consumption rate and metabolomics were examined as mechanistic endpoints. In vivo plasma concentrations of IACS-010759 in mice were determined by LC-MS to select a dose that reflected clinically attainable concentrations. RESULTS: In vitro, the combination of AZD3965 and IACS-010759 is synergistic and induces DLBCL cell death, whereas monotherapy treatments induce a cytostatic response. Significant anti-tumour activity was evident in Toledo and Farage models when the two inhibitors were administered concurrently despite limited or no effect on the growth of DLBCL xenografts as monotherapies. CONCLUSIONS: This is the first study to examine a combination of two distinct approaches to targeting tumour metabolism in DLBCL xenografts. Whilst nanomolar concentrations of either AZD3965 or IACS-010759 monotherapy demonstrate anti-proliferative activity against DLBCL cell lines in vitro, appreciable clinical activity in DLBCL patients may only be realised through their combined use.
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spelling pubmed-94281792022-09-01 Simultaneous targeting of glycolysis and oxidative phosphorylation as a therapeutic strategy to treat diffuse large B-cell lymphoma Noble, Richard A. Thomas, Huw Zhao, Yan Herendi, Lili Howarth, Rachel Dragoni, Ilaria Keun, Hector C. Vellano, Christopher P. Marszalek, Joseph R. Wedge, Stephen R. Br J Cancer Article BACKGROUND: We evaluated the therapeutic potential of combining the monocarboxylate transporter 1 (MCT1) inhibitor AZD3965 with the mitochondrial respiratory Complex I inhibitor IACS-010759, for the treatment of diffuse large B-cell lymphoma (DLBCL), a potential clinically actionable strategy to target tumour metabolism. METHODS: AZD3965 and IACS-010759 sensitivity were determined in DLBCL cell lines and tumour xenograft models. Lactate concentrations, oxygen consumption rate and metabolomics were examined as mechanistic endpoints. In vivo plasma concentrations of IACS-010759 in mice were determined by LC-MS to select a dose that reflected clinically attainable concentrations. RESULTS: In vitro, the combination of AZD3965 and IACS-010759 is synergistic and induces DLBCL cell death, whereas monotherapy treatments induce a cytostatic response. Significant anti-tumour activity was evident in Toledo and Farage models when the two inhibitors were administered concurrently despite limited or no effect on the growth of DLBCL xenografts as monotherapies. CONCLUSIONS: This is the first study to examine a combination of two distinct approaches to targeting tumour metabolism in DLBCL xenografts. Whilst nanomolar concentrations of either AZD3965 or IACS-010759 monotherapy demonstrate anti-proliferative activity against DLBCL cell lines in vitro, appreciable clinical activity in DLBCL patients may only be realised through their combined use. Nature Publishing Group UK 2022-05-26 2022-09-01 /pmc/articles/PMC9428179/ /pubmed/35618788 http://dx.doi.org/10.1038/s41416-022-01848-w Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Noble, Richard A.
Thomas, Huw
Zhao, Yan
Herendi, Lili
Howarth, Rachel
Dragoni, Ilaria
Keun, Hector C.
Vellano, Christopher P.
Marszalek, Joseph R.
Wedge, Stephen R.
Simultaneous targeting of glycolysis and oxidative phosphorylation as a therapeutic strategy to treat diffuse large B-cell lymphoma
title Simultaneous targeting of glycolysis and oxidative phosphorylation as a therapeutic strategy to treat diffuse large B-cell lymphoma
title_full Simultaneous targeting of glycolysis and oxidative phosphorylation as a therapeutic strategy to treat diffuse large B-cell lymphoma
title_fullStr Simultaneous targeting of glycolysis and oxidative phosphorylation as a therapeutic strategy to treat diffuse large B-cell lymphoma
title_full_unstemmed Simultaneous targeting of glycolysis and oxidative phosphorylation as a therapeutic strategy to treat diffuse large B-cell lymphoma
title_short Simultaneous targeting of glycolysis and oxidative phosphorylation as a therapeutic strategy to treat diffuse large B-cell lymphoma
title_sort simultaneous targeting of glycolysis and oxidative phosphorylation as a therapeutic strategy to treat diffuse large b-cell lymphoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9428179/
https://www.ncbi.nlm.nih.gov/pubmed/35618788
http://dx.doi.org/10.1038/s41416-022-01848-w
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