search button
Open Access

Hypoxia increases chemoresistance in human medulloblastoma DAOY cells via hypoxia‑inducible factor 1α‑mediated downregulation of the CYP2B6, CYP3A4 and CYP3A5 enzymes and inhibition of cell proliferation

  • Authors:
    • Jesús Valencia‑Cervantes
    • Sara Huerta‑Yepez
    • Guillermo Aquino‑Jarquín
    • Sara Rodríguez‑Enríquez
    • Daniel Martínez‑Fong
    • José‑Antonio Arias‑Montaño
    • Víctor Manuel Dávila‑Borja

  • View Affiliations

  • Published online on: October 12, 2018     https://doi.org/10.3892/or.2018.6790
  • Pages: 178-190

  • Copyright: © Valencia‑Cervantes et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Medulloblastomas are among the most frequently diagnosed pediatric solid tumors, and drug resistance remains as the principal cause of treatment failure. Hypoxia and the subsequent activation of hypoxia‑inducible factor 1α (HIF‑1α) are considered key factors in modulating drug antitumor effectiveness, but the underlying mechanisms in medulloblastomas have not yet been clearly understood. The aim of the present study was to determine whether hypoxia induces resistance to cyclophosphamide (CPA) and ifosfamide (IFA) in DAOY medulloblastoma cells, whether the mechanism is dependent on HIF‑1α, and whether involves the modulation of the expression of cytochromes P450 (CYP)2B6, 3A4 and 3A5 and the control of cell proliferation. Monolayer cultures of DAOY medulloblastoma cells were exposed for 24 h to moderate (1% O2) or severe (0.1% O2) hypoxia, and protein expression was evaluated by immunoblotting. Cytotoxicity was studied with the MTT assay and by Annexin V/PI staining and flow cytometry. Cell proliferation was determined by the trypan‑blue exclusion assay and cell cycle by propidium iodide staining and flow cytometry. Hypoxia decreased CPA and IFA cytotoxicity in medulloblastoma cells, which correlated with a reduction in the protein levels of CYP2B6, CYP3A4 and CYP3A5 and inhibition of cell proliferation. These responses were dependent on hypoxia‑induced HIF‑1α activation, as evidenced by chemical inhibition of its transcriptional activity with 2‑methoxyestradiol (2‑ME), which enhanced the cytotoxic activity of CPA and IFA and increased apoptosis. Our results indicate that by stimulating HIF‑1α activity, hypoxia downregulates the expression of CYP2B6, CYP3A4 and CYP3A5, that in turn leads to decreased conversion of CPA and IFA into their active forms and thus to diminished cytotoxicity. These results support that the combination of HIF‑1α inhibitors and canonical antineoplastic agents provides a potential therapeutic alternative against medulloblastoma.
View Figures
View References

Related Articles

Journal Cover

January-2019
Volume 41 Issue 1

Print ISSN: 1021-335X
Online ISSN:1791-2431

Sign up for eToc alerts

Recommend to Library

  • Journal Metrics
  • Impact Factor: 4.2
  • Ranked Oncology
    (total number of cites)
  • CiteScore: 8.4
  • CiteScore Rank: Q1: #68/366 Oncology
  • Source Normalized Impact per Paper (SNIP): 0.786
  • SCImago Journal Rank (SJR): 0.812
International Symposium on Molecular Medicine Conference Banner
The Cancer Story
World Congress on Advances in Oncology and International Symposium on Molecular Medicine Conference Banner
World Academy Of Sciences Banner
Heyday Road Banner

0

Copy and paste a formatted citation
x
Spandidos Publications style
Valencia‑Cervantes J, Huerta‑Yepez S, Aquino‑Jarquín G, Rodríguez‑Enríquez S, Martínez‑Fong D, Arias‑Montaño JA and Dávila‑Borja VM: Hypoxia increases chemoresistance in human medulloblastoma DAOY cells via hypoxia‑inducible factor 1α‑mediated downregulation of the CYP2B6, CYP3A4 and CYP3A5 enzymes and inhibition of cell proliferation. Oncol Rep 41: 178-190, 2019
APA
Valencia‑Cervantes, J., Huerta‑Yepez, S., Aquino‑Jarquín, G., Rodríguez‑Enríquez, S., Martínez‑Fong, D., Arias‑Montaño, J., & Dávila‑Borja, V.M. (2019). Hypoxia increases chemoresistance in human medulloblastoma DAOY cells via hypoxia‑inducible factor 1α‑mediated downregulation of the CYP2B6, CYP3A4 and CYP3A5 enzymes and inhibition of cell proliferation. Oncology Reports, 41, 178-190. https://doi.org/10.3892/or.2018.6790
MLA
Valencia‑Cervantes, J., Huerta‑Yepez, S., Aquino‑Jarquín, G., Rodríguez‑Enríquez, S., Martínez‑Fong, D., Arias‑Montaño, J., Dávila‑Borja, V. M."Hypoxia increases chemoresistance in human medulloblastoma DAOY cells via hypoxia‑inducible factor 1α‑mediated downregulation of the CYP2B6, CYP3A4 and CYP3A5 enzymes and inhibition of cell proliferation". Oncology Reports 41.1 (2019): 178-190.
Chicago
Valencia‑Cervantes, J., Huerta‑Yepez, S., Aquino‑Jarquín, G., Rodríguez‑Enríquez, S., Martínez‑Fong, D., Arias‑Montaño, J., Dávila‑Borja, V. M."Hypoxia increases chemoresistance in human medulloblastoma DAOY cells via hypoxia‑inducible factor 1α‑mediated downregulation of the CYP2B6, CYP3A4 and CYP3A5 enzymes and inhibition of cell proliferation". Oncology Reports 41, no. 1 (2019): 178-190. https://doi.org/10.3892/or.2018.6790