دورية أكاديمية
Simultaneous targeting of glycolysis and oxidative phosphorylation as a therapeutic strategy to treat diffuse large B-cell lymphoma
| العنوان: | Simultaneous targeting of glycolysis and oxidative phosphorylation as a therapeutic strategy to treat diffuse large B-cell lymphoma |
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| المؤلفون: | 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. |
| المساهمون: | Cancer Research UK |
| المصدر: | British Journal of Cancer ; volume 127, issue 5, page 937-947 ; ISSN 0007-0920 1532-1827 |
| بيانات النشر: | Springer Science and Business Media LLC |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | Cancer Research, Oncology |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1038/s41416-022-01848-w |
| الإتاحة: | https://doi.org/10.1038/s41416-022-01848-wTest https://www.nature.com/articles/s41416-022-01848-w.pdfTest https://www.nature.com/articles/s41416-022-01848-wTest |
| حقوق: | https://creativecommons.org/licenses/by/4.0Test ; https://creativecommons.org/licenses/by/4.0Test |
| رقم الانضمام: | edsbas.B3498F6F |
| قاعدة البيانات: | BASE |
| DOI: | 10.1038/s41416-022-01848-w |
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