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

Authors
Rho, Jin KyungChoi, Yun JungLee, Jin KyungRyoo, Baek-YeolIl Na, ImYang, Sung HyunKim, Cheol HyeonDo Yoo, YoungLee, Jae Cheol
Issue Date
Mar-2009
Publisher
SPANDIDOS PUBL LTD
Keywords
gefitinib; epidermal growth factor receptor; hypoxia; hypoxia-inducible factor-1 alpha; lung cancer; resistance
Citation
ONCOLOGY REPORTS, v.21, no.3, pp.801 - 807
Indexed
SCIE
SCOPUS
Journal Title
ONCOLOGY REPORTS
Volume
21
Number
3
Start Page
801
End Page
807
URI
https://scholar.korea.ac.kr/handle/2021.sw.korea/120458
DOI
10.3892/or_00000287
ISSN
1021-335X
Abstract
Hypoxia-inducible factor-1 alpha (HIF-1 alpha) 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-1 alpha protein accumulation. Thus, we hypothesized that an EGFR-TK inhibitor, gefitinib, might circumvent the hypoxia-induced drug resistance via the regulation of HIF-1 alpha expression. In our data, treatment of gefitinib suppressed induced HIF-alpha by hypoxia. This action of gefitinib was caused by reduced protein stability without any change in the level of HIF-1 alpha mRNA. The effect of gefitinib on down-regulation of HIF-1 alpha 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-1 alpha expression. In addition, the suppression of HIF-1 alpha 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-1 alpha by the inhibition of EGFR-Akt pathway may overcome the hypoxia-induced drug resistance.
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