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HIF-1 stabilization exerts anticancer effects in breast cancer cells in vitro and in vivo.

Authors
  • Kachamakova-Trojanowska, Neli1
  • Podkalicka, Paulina2
  • Bogacz, Tomasz2
  • Barwacz, Szymon2
  • Józkowicz, Alicja2
  • Dulak, Józef2
  • Łoboda, Agnieszka3
  • 1 Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Kraków, Poland; Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7a, 30-387 Kraków, Poland. , (Poland)
  • 2 Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Kraków, Poland. , (Poland)
  • 3 Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Kraków, Poland. Electronic address: [email protected] , (Poland)
Type
Published Article
Journal
Biochemical pharmacology
Publisher
New York, NY : Elsevier Science Inc
Publication Date
Mar 20, 2020
Pages
113922–113922
Identifiers
DOI: 10.1016/j.bcp.2020.113922
PMID: 32205093
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Tumor hypoxia and high activity of hypoxia-inducible factor-1 (HIF-1) correlate with adverse disease outcomes, malignancy, resistance to therapy and metastasis. Nonetheless, recent studies indicate that under certain circumstances, HIF-1 stabilization may exert protective effects and even decrease tumor cell aggressiveness. This study aimed to characterize the potential anticancer effect of molidustat (BAY 85-3934), the prolyl hydroxylase (PHD) inhibitor and HIF-1 stabilizator. We confirmed that molidustat stabilizes HIF-1α and induces the expression of vascular endothelial growth factor (VEGF) in MDA-MB-231 breast cancer cells, to a similar or even greater extent than hypoxia. Interestingly, decreased cell survival and colony formation capabilities, together with S/G2 cell cycle arrest, were observed after treatment with PHD inhibitor. Importantly, molidustat enhanced the effectiveness of the chemotherapeutic drug, gemcitabine, on cancer cells. Finally, the xenograft model revealed decreased tumor growth in vivo after molidustat treatment. Both in vitro and in vivo analysis showed no differences in the angiogenic potential of endothelial cells treated with tumor-conditioned media or vascularization of the MDA-MB-231 xenografts, respectively. In summary, molidustat treatment exhibits an inhibitory effect on breast cancer cell survival, self-renewal capacity and potentiates the efficacy of chemotherapeutic gemcitabine. Copyright © 2020. Published by Elsevier Inc.

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