Display options
Cite
Lo Dico A, Valtorta S, Ottobrini L, et al. Role of Metformin and AKT Axis Modulation in the Reversion of Hypoxia Induced TMZ-Resistance in Glioma Cells. Front Oncol. 2019;9:463doi: 10.3389/fonc.2019.00463.
Lo Dico, A., Valtorta, S., Ottobrini, L., & Moresco, R. M. (2019). Role of Metformin and AKT Axis Modulation in the Reversion of Hypoxia Induced TMZ-Resistance in Glioma Cells. Frontiers in oncology, 9463. https://doi.org/10.3389/fonc.2019.00463
Lo Dico, Alessia, et al. "Role of Metformin and AKT Axis Modulation in the Reversion of Hypoxia Induced TMZ-Resistance in Glioma Cells." Frontiers in oncology vol. 9 (2019): 463. doi: https://doi.org/10.3389/fonc.2019.00463
Lo Dico A, Valtorta S, Ottobrini L, Moresco RM. Role of Metformin and AKT Axis Modulation in the Reversion of Hypoxia Induced TMZ-Resistance in Glioma Cells. Front Oncol. 2019 May 31;9:463. doi: 10.3389/fonc.2019.00463. eCollection 2019. PMID: 31214505; PMCID: PMC6554426.
Copy Download .nbib Format: NLM
Share it on

Front Oncol. 2019 May 31;9:463. doi: 10.3389/fonc.2019.00463. eCollection 2019.

Role of Metformin and AKT Axis Modulation in the Reversion of Hypoxia Induced TMZ-Resistance in Glioma Cells.

Frontiers in oncology

Alessia Lo Dico, Silvia Valtorta, Luisa Ottobrini, Rosa Maria Moresco

Affiliations

  1. Department of Pathophysiology and Transplantation (DEPT), University of Milan, Milan, Italy.
  2. Institute of Molecular Bioimaging and Physiology (IBFM), National Research Council (CNR), Segrate, Italy.
  3. Tecnomed Foundation, Medicine and Surgery Department, University of Milano- Bicocca, Monza, Italy.
  4. Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy.

PMID: 31214505 PMCID: PMC6554426 DOI: 10.3389/fonc.2019.00463

Abstract

Hypoxia is a key driver of tumor adaptation promoting tumor progression and resistance to therapy. Hypoxia related pathways might represent attractive targets for the treatment of Glioblastoma Multiforme (GBM), that up to date is characterized by a poor prognosis. Primary aim of this study was to investigate the role of hypoxia and hypoxia-related modifications in the effect of temozolomide (TMZ) given alone or in association with the antidiabetic agent Metformin (MET) or the PI3K/mTOR blocker, BEZ235. The study was conducted in the TMZ responsive U251 and resistant T98 GBM cells. Our results showed that during hypoxia, TMZ plus MET reduced viability of U251 cells affecting also CD133 and CD90 expressing cells. This effect was associated with a reduction of HIF-1α activity, VEGF release and AKT activation. In T98 TMZ-resistant cells, TMZ plus MET exerted similar effects on HIF-1α. However, in this cell line, TMZ plus MET failed to reduce CD133 positive cells and AKT phosphorylation. Nevertheless, the administration of the dual PI3K/mTOR inhibitor BEZ235 potentiated the effect of TMZ plus MET on cell viability, inducing a pro-apoptotic phenotype during hypoxic condition also in T98 cells, suggesting the block of the PI3K/AKT/mTOR pathway as a complementary target to further overcome GBM resistance during hypoxia. In conclusion, we proposed TMZ plus MET as suitable treatment to revert TMZ-resistance also during hypoxia, an effect potentiated by the inhibition of PI3K/mTOR axis.

Keywords: AKT pathway; HIF-1α biomarker; MET; TMZ responsiveness; hypoxia resistance

References

  1. Mol Cell Biol. 2003 Nov;23(22):8306-15 - PubMed
  2. Brain Pathol. 2004 Oct;14(4):372-7 - PubMed
  3. N Engl J Med. 2005 Mar 10;352(10):987-96 - PubMed
  4. Cancer Res. 2005 Jun 1;65(11):4861-9 - PubMed
  5. Mol Cancer Res. 2006 Jul;4(7):471-9 - PubMed
  6. Oncogene. 2008 Sep 18;27(41):5511-26 - PubMed
  7. Mol Cancer Ther. 2009 Aug;8(8):2204-10 - PubMed
  8. Oncogene. 2009 Nov 12;28(45):3949-59 - PubMed
  9. Proc Natl Acad Sci U S A. 2009 Dec 29;106(52):22299-304 - PubMed
  10. Brain. 2010 Apr;133(Pt 4):983-95 - PubMed
  11. Mol Cancer. 2010 Jun 01;9:135 - PubMed
  12. Neoplasia. 2010 Jun;12(6):453-63 - PubMed
  13. J Biol Chem. 2010 Dec 24;285(52):40461-71 - PubMed
  14. Neoplasia. 2012 Jan;14(1):34-43 - PubMed
  15. Stem Cells Transl Med. 2012 Nov;1(11):811-24 - PubMed
  16. Cell Cycle. 2013 Jan 1;12(1):145-56 - PubMed
  17. Mol Cancer Ther. 2013 May;12(5):577-88 - PubMed
  18. Int J Med Sci. 2013;10(4):399-407 - PubMed
  19. Mol Imaging Biol. 2014 Apr;16(2):210-23 - PubMed
  20. Adv Exp Med Biol. 2014;772:1-39 - PubMed
  21. Proc Natl Acad Sci U S A. 2014 Jan 28;111(4):E435-44 - PubMed
  22. Eur J Nucl Med Mol Imaging. 2015 Jun;42(7):1093-105 - PubMed
  23. Cancer Lett. 2015 Oct 10;367(1):58-68 - PubMed
  24. Cancer Cell. 2016 Aug 8;30(2):257-272 - PubMed
  25. Oncol Lett. 2016 Oct;12(4):2283-2288 - PubMed
  26. Oncotarget. 2016 Nov 29;7(48):78787-78803 - PubMed
  27. Am J Transl Res. 2016 Nov 15;8(11):4812-4821 - PubMed
  28. Chin J Cancer. 2017 Jan 26;36(1):17 - PubMed
  29. Mol Cancer. 2017 Apr 13;16(1):79 - PubMed
  30. Cells. 2017 Nov 22;6(4):null - PubMed
  31. Cancer Res Treat. 2018 Oct;50(4):1331-1342 - PubMed
  32. Oncotarget. 2017 Dec 6;8(68):113090-113104 - PubMed

Publication Types