In Vitro and In Vivo Characterization of MCT1 Inhibitor AZD3965 Confirms Preclinical Safety Compatible with Breast Cancer Treatment
To survive and proliferate in solid tumors, cancer cells adapt and evolve rapidly in microenvironments where oxygen and substrate bioavailability fluctuates over time and space. This creates metabolic heterogeneity. Cancer cells can further cooperate metabolically, for example by swapping glycolytic...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-02-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/3/569 |
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| author | Zohra Benyahia Marine C. N. M. Blackman Loïc Hamelin Luca X. Zampieri Tania Capeloa Marie L. Bedin Thibaut Vazeille Olivier Schakman Pierre Sonveaux |
| author_facet | Zohra Benyahia Marine C. N. M. Blackman Loïc Hamelin Luca X. Zampieri Tania Capeloa Marie L. Bedin Thibaut Vazeille Olivier Schakman Pierre Sonveaux |
| author_sort | Zohra Benyahia |
| collection | DOAJ |
| description | To survive and proliferate in solid tumors, cancer cells adapt and evolve rapidly in microenvironments where oxygen and substrate bioavailability fluctuates over time and space. This creates metabolic heterogeneity. Cancer cells can further cooperate metabolically, for example by swapping glycolytic end-product lactate for blood-borne glucose. This type of cooperation can be targeted therapeutically, since transmembrane lactate exchanges are facilitated by lactate-proton symporters of the monocarboxylate (MCT) family. Among new drugs, AZD3965 is a first-in-class selective MCT1 inhibitor currently tested in Phase I/II clinical trials for patients with different types of cancers. Because MCT1 can function bidirectionally, we tested here whether and how malignant and nonmalignant cells adapt their metabolism and MCT repertoire when AZD3965 inhibits either lactate import or export. Using breast-associated malignant and nonmalignant cell lines as models, we report that AZD3965 is not directly cytotoxic. In the presence of glucose and glutamine, oxidative cells can survive when lactate uptake is blocked, and proliferating cells compensate MCT1 inhibition by overexpressing MCT4, a specialized facilitator of lactate export. Phenotypic characterization of mice focusing on metabolism, muscle and brain physiology found partial and transient memory retention defect as sole consequence of MCT1 inhibition by AZD3965. We therefore conclude that AZD3965 is compatible with anticancer therapy. |
| first_indexed | 2024-03-09T06:07:26Z |
| format | Article |
| id | doaj.art-98671d29eb7d4548af0c17cacdacd454 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T06:07:26Z |
| publishDate | 2021-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-98671d29eb7d4548af0c17cacdacd4542023-12-03T12:01:54ZengMDPI AGCancers2072-66942021-02-0113356910.3390/cancers13030569In Vitro and In Vivo Characterization of MCT1 Inhibitor AZD3965 Confirms Preclinical Safety Compatible with Breast Cancer TreatmentZohra Benyahia0Marine C. N. M. Blackman1Loïc Hamelin2Luca X. Zampieri3Tania Capeloa4Marie L. Bedin5Thibaut Vazeille6Olivier Schakman7Pierre Sonveaux8Pole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), Avenue Hippocrate 57 box B1.57.04, 1200 Brussels, BelgiumPole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), Avenue Hippocrate 57 box B1.57.04, 1200 Brussels, BelgiumPole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), Avenue Hippocrate 57 box B1.57.04, 1200 Brussels, BelgiumPole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), Avenue Hippocrate 57 box B1.57.04, 1200 Brussels, BelgiumPole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), Avenue Hippocrate 57 box B1.57.04, 1200 Brussels, BelgiumPole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), Avenue Hippocrate 57 box B1.57.04, 1200 Brussels, BelgiumPole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), Avenue Hippocrate 57 box B1.57.04, 1200 Brussels, BelgiumPole of Cell Physiology, Institut des Neurosciences (IoNS), Université Catholique de Louvain (UCLouvain), Avenue E. Mounier 53 box B1.53.17, 1200 Brussels, BelgiumPole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), Avenue Hippocrate 57 box B1.57.04, 1200 Brussels, BelgiumTo survive and proliferate in solid tumors, cancer cells adapt and evolve rapidly in microenvironments where oxygen and substrate bioavailability fluctuates over time and space. This creates metabolic heterogeneity. Cancer cells can further cooperate metabolically, for example by swapping glycolytic end-product lactate for blood-borne glucose. This type of cooperation can be targeted therapeutically, since transmembrane lactate exchanges are facilitated by lactate-proton symporters of the monocarboxylate (MCT) family. Among new drugs, AZD3965 is a first-in-class selective MCT1 inhibitor currently tested in Phase I/II clinical trials for patients with different types of cancers. Because MCT1 can function bidirectionally, we tested here whether and how malignant and nonmalignant cells adapt their metabolism and MCT repertoire when AZD3965 inhibits either lactate import or export. Using breast-associated malignant and nonmalignant cell lines as models, we report that AZD3965 is not directly cytotoxic. In the presence of glucose and glutamine, oxidative cells can survive when lactate uptake is blocked, and proliferating cells compensate MCT1 inhibition by overexpressing MCT4, a specialized facilitator of lactate export. Phenotypic characterization of mice focusing on metabolism, muscle and brain physiology found partial and transient memory retention defect as sole consequence of MCT1 inhibition by AZD3965. We therefore conclude that AZD3965 is compatible with anticancer therapy.https://www.mdpi.com/2072-6694/13/3/569breast cancercancer metabolismoxidative phosphorylation (OXPHOS)oxidative pathway of lactatemonocarboxylate transporters (MCTs)CD147/basigin |
| spellingShingle | Zohra Benyahia Marine C. N. M. Blackman Loïc Hamelin Luca X. Zampieri Tania Capeloa Marie L. Bedin Thibaut Vazeille Olivier Schakman Pierre Sonveaux In Vitro and In Vivo Characterization of MCT1 Inhibitor AZD3965 Confirms Preclinical Safety Compatible with Breast Cancer Treatment Cancers breast cancer cancer metabolism oxidative phosphorylation (OXPHOS) oxidative pathway of lactate monocarboxylate transporters (MCTs) CD147/basigin |
| title | In Vitro and In Vivo Characterization of MCT1 Inhibitor AZD3965 Confirms Preclinical Safety Compatible with Breast Cancer Treatment |
| title_full | In Vitro and In Vivo Characterization of MCT1 Inhibitor AZD3965 Confirms Preclinical Safety Compatible with Breast Cancer Treatment |
| title_fullStr | In Vitro and In Vivo Characterization of MCT1 Inhibitor AZD3965 Confirms Preclinical Safety Compatible with Breast Cancer Treatment |
| title_full_unstemmed | In Vitro and In Vivo Characterization of MCT1 Inhibitor AZD3965 Confirms Preclinical Safety Compatible with Breast Cancer Treatment |
| title_short | In Vitro and In Vivo Characterization of MCT1 Inhibitor AZD3965 Confirms Preclinical Safety Compatible with Breast Cancer Treatment |
| title_sort | in vitro and in vivo characterization of mct1 inhibitor azd3965 confirms preclinical safety compatible with breast cancer treatment |
| topic | breast cancer cancer metabolism oxidative phosphorylation (OXPHOS) oxidative pathway of lactate monocarboxylate transporters (MCTs) CD147/basigin |
| url | https://www.mdpi.com/2072-6694/13/3/569 |
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