Gefitinib circumvents hypoxia-induced drug resistance by the modulation of HIF-1α

  • Authors:
    • Jin Kyung Rho
    • Yun Jung Choi
    • Jin Kyung Lee
    • Baek-Yeol Ryoo
    • Im Ii Na
    • Sung Hyun Yang
    • Cheol Hyeon Kim
    • Young Do Yoo
    • Jae Cheol Lee
  • View Affiliations

  • Published online on: March 1, 2009     https://doi.org/10.3892/or_00000287
  • Pages: 801-807
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Abstract

Hypoxia-inducible factor-1α (HIF-1α) is a transcriptional factor which is activated by hypoxia and associated with cell survival, proliferation and drug resistance. Recent studies have shown that the down-stream molecules of the epidermal growth factor receptor (EGFR) signal are involved in the hypoxia-dependent or -independent HIF-1α protein accumulation. Thus, we hypothesized that an EGFR-TK inhibitor, gefitinib, might circumvent the hypoxia-induced drug resistance via the regulation of HIF-1α expression. In our data, treatment of gefitinib suppressed induced HIF-1α by hypoxia. This action of gefitinib was caused by reduced protein stability without any change in the level of HIF-1α mRNA. The effect of gefitinib on down-regulation of HIF-1α was reversed by transfection of constitutively active form of Akt. The cellular response to gefitinib was similar in both normoxia and hypoxia condition. However, the response to conventional chemotherapeutic drugs decreased >50% under hypoxia condition and they did not change HIF-1α expression. In addition, the suppression of HIF-1α using siRNA overcame partially hypoxia-induced drug resistance. In conclusion, gefitinib was able to circumvent hypoxia-induced drug resistance suggesting that the effective suppression of HIF-1α by the inhibition of EGFR-Akt pathway may overcome the hypoxia-induced drug resistance.

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March 2009
Volume 21 Issue 3

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

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Spandidos Publications style
Rho JK, Choi YJ, Lee JK, Ryoo B, Na II, Yang SH, Kim CH, Yoo YD and Lee JC: Gefitinib circumvents hypoxia-induced drug resistance by the modulation of HIF-1α. Oncol Rep 21: 801-807, 2009.
APA
Rho, J.K., Choi, Y.J., Lee, J.K., Ryoo, B., Na, I.I., Yang, S.H. ... Lee, J.C. (2009). Gefitinib circumvents hypoxia-induced drug resistance by the modulation of HIF-1α. Oncology Reports, 21, 801-807. https://doi.org/10.3892/or_00000287
MLA
Rho, J. K., Choi, Y. J., Lee, J. K., Ryoo, B., Na, I. I., Yang, S. H., Kim, C. H., Yoo, Y. D., Lee, J. C."Gefitinib circumvents hypoxia-induced drug resistance by the modulation of HIF-1α". Oncology Reports 21.3 (2009): 801-807.
Chicago
Rho, J. K., Choi, Y. J., Lee, J. K., Ryoo, B., Na, I. I., Yang, S. H., Kim, C. H., Yoo, Y. D., Lee, J. C."Gefitinib circumvents hypoxia-induced drug resistance by the modulation of HIF-1α". Oncology Reports 21, no. 3 (2009): 801-807. https://doi.org/10.3892/or_00000287