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Benyahia Z, Blackman MCNM, Hamelin L, et al. In Vitro and In Vivo Characterization of MCT1 Inhibitor AZD3965 Confirms Preclinical Safety Compatible with Breast Cancer Treatment. Cancers (Basel). 2021;13(3)doi: 10.3390/cancers13030569.
Benyahia, Z., Blackman, M. C. N. M., Hamelin, L., Zampieri, L. X., Capeloa, T., Bedin, M. L., Vazeille, T., Schakman, O., & Sonveaux, P. (2021). In Vitro and In Vivo Characterization of MCT1 Inhibitor AZD3965 Confirms Preclinical Safety Compatible with Breast Cancer Treatment. Cancers, 13(3), . https://doi.org/10.3390/cancers13030569
Benyahia, Zohra, et al. "In Vitro and In Vivo Characterization of MCT1 Inhibitor AZD3965 Confirms Preclinical Safety Compatible with Breast Cancer Treatment." Cancers vol. 13,3 (2021). doi: https://doi.org/10.3390/cancers13030569
Benyahia Z, Blackman MCNM, Hamelin L, Zampieri LX, Capeloa T, Bedin ML, Vazeille T, Schakman O, Sonveaux P. In Vitro and In Vivo Characterization of MCT1 Inhibitor AZD3965 Confirms Preclinical Safety Compatible with Breast Cancer Treatment. Cancers (Basel). 2021 Feb 02;13(3). doi: 10.3390/cancers13030569. PMID: 33540599; PMCID: PMC7867268.
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Cancers (Basel). 2021 Feb 02;13(3). doi: 10.3390/cancers13030569.

In Vitro and In Vivo Characterization of MCT1 Inhibitor AZD3965 Confirms Preclinical Safety Compatible with Breast Cancer Treatment.

Cancers

Zohra Benyahia, Marine C N M Blackman, Loïc Hamelin, Luca X Zampieri, Tania Capeloa, Marie L Bedin, Thibaut Vazeille, Olivier Schakman, Pierre Sonveaux

Affiliations

  1. Pole 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, Belgium.
  2. Pole of Cell Physiology, Institut des Neurosciences (IoNS), Université Catholique de Louvain (UCLouvain), Avenue E. Mounier 53 box B1.53.17, 1200 Brussels, Belgium.

PMID: 33540599 PMCID: PMC7867268 DOI: 10.3390/cancers13030569

Abstract

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.

Keywords: CD147/basigin; brain; breast cancer; cancer metabolism; heart; monocarboxylate transporters (MCTs); muscle; oxidative pathway of lactate; oxidative phosphorylation (OXPHOS); preclinical toxicology

References

  1. J Biol Chem. 2005 Jul 22;280(29):27213-21 - PubMed
  2. Pharm Res. 2019 Dec 10;37(1):5 - PubMed
  3. Am J Physiol Cell Physiol. 2001 May;280(5):C1319-26 - PubMed
  4. Clin Cancer Res. 2014 Feb 15;20(4):926-937 - PubMed
  5. Cell Rep. 2016 May 10;15(6):1161-74 - PubMed
  6. Int J Radiat Oncol Biol Phys. 2001 Nov 1;51(3):840-8 - PubMed
  7. Nat Chem Biol. 2005 Dec;1(7):371-6 - PubMed
  8. Nature. 2011 Nov 20;481(7381):385-8 - PubMed
  9. Nature. 2017 Nov 2;551(7678):115-118 - PubMed
  10. Oncogene. 2014 Jul 31;33(31):4060-8 - PubMed
  11. Anticancer Res. 2001 Nov-Dec;21(6B):4317-24 - PubMed
  12. Adv Healthc Mater. 2020 May 19;:e2000549 - PubMed
  13. Cancer Res. 2007 Feb 1;67(3):854-5 - PubMed
  14. BMC Cancer. 2011 Aug 07;11:341 - PubMed
  15. Mamm Genome. 2005 Nov;16(11):829-37 - PubMed
  16. Adv Exp Med Biol. 2020;1219:51-74 - PubMed
  17. J Physiol. 2000 Dec 1;529 Pt 2:285-93 - PubMed
  18. J Neurosci Res. 2003 Jul 15;73(2):141-55 - PubMed
  19. J Clin Pathol. 1962 Nov;15:579-84 - PubMed
  20. Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19345-50 - PubMed
  21. Science. 1998 Jan 16;279(5349):349-52 - PubMed
  22. Oncotarget. 2017 May 25;8(41):69219-69236 - PubMed
  23. Mol Biosyst. 2017 Feb 28;13(3):498-509 - PubMed
  24. Experientia. 1996 May 15;52(5):464-8 - PubMed
  25. Br J Cancer. 2020 Apr;122(8):1272 - PubMed
  26. PLoS One. 2012;7(3):e33418 - PubMed
  27. Semin Cancer Biol. 2017 Apr;43:66-73 - PubMed
  28. Mol Aspects Med. 2013 Apr-Jun;34(2-3):337-49 - PubMed
  29. J Clin Pathol. 2016 Mar;69(3):209-14 - PubMed
  30. J Biol Chem. 2006 Apr 7;281(14):9030-7 - PubMed
  31. Eur J Appl Physiol. 2001 Nov;86(1):12-6 - PubMed
  32. Cancer Cell. 2016 Sep 12;30(3):418-431 - PubMed
  33. Eur J Med Chem. 2020 Aug 1;199:112393 - PubMed
  34. Cancer Res. 2014 Oct 1;74(19):5507-19 - PubMed
  35. Science. 2009 May 22;324(5930):1029-33 - PubMed
  36. J Clin Invest. 2008 Dec;118(12):3930-42 - PubMed
  37. Cell. 2011 Mar 4;144(5):810-23 - PubMed
  38. Cancer Res. 1990 Sep 15;50(18):6075-86 - PubMed
  39. Cell Rep. 2016 May 10;15(6):1144-60 - PubMed
  40. Mol Cancer Res. 2020 Sep;18(9):1379-1391 - PubMed
  41. Prostate. 2013 May;73(7):763-9 - PubMed
  42. Mol Metab. 2020 Mar;33:48-66 - PubMed
  43. PLoS One. 2013 Dec 18;8(12):e82505 - PubMed
  44. J Natl Cancer Inst. 2000 Dec 6;92(23):1941-2 - PubMed
  45. Biochem J. 2000 Aug 15;350 Pt 1:219-27 - PubMed
  46. Biochem J. 2015 Feb 15;466(1):177-88 - PubMed
  47. Curr Opin Genet Dev. 2010 Feb;20(1):51-6 - PubMed
  48. Cancer. 2009 Oct 15;115(20):4655-66 - PubMed
  49. J Intern Med. 2013 Feb;273(2):156-65 - PubMed
  50. Br J Pharmacol. 2020 Oct;177(20):4734-4749 - PubMed
  51. Oncol Lett. 2017 Jun;13(6):4708-4712 - PubMed
  52. Cell Rep. 2016 Feb 23;14(7):1590-1601 - PubMed
  53. Cell Rep. 2016 May 10;15(6):1134-43 - PubMed
  54. Front Pharmacol. 2015 Oct 13;6:228 - PubMed
  55. Int J Radiat Oncol Biol Phys. 1988 Sep;15(3):691-7 - PubMed
  56. Cell Cycle. 2012 Nov 1;11(21):3956-63 - PubMed
  57. Front Oncol. 2018 Feb 07;8:22 - PubMed
  58. Biochem J. 2010 Oct 15;431(2):217-25 - PubMed
  59. Cancer Res. 2014 Feb 1;74(3):908-20 - PubMed
  60. Br J Cancer. 1955 Dec;9(4):539-49 - PubMed
  61. BMC Cancer. 2020 May 25;20(1):470 - PubMed
  62. Histopathology. 2010 Jun;56(7):860-7 - PubMed
  63. J Pharm Biomed Anal. 2018 Jun 5;155:270-275 - PubMed
  64. AAPS J. 2019 Jan 7;21(2):13 - PubMed
  65. Proc Natl Acad Sci U S A. 2011 Oct 4;108(40):16663-8 - PubMed

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