HIF-1 signaling in drug resistance to chemotherapy

N. A. Warfel, W. S. El-Deiry

Research output: Contribution to journalReview articlepeer-review

83 Scopus citations

Abstract

Activation of hypoxia-inducible factor 1 (HIF-1) signaling is observed in a broad range of human cancers due to tumor hypoxia and epigenetic mechanisms. HIF-1 activation leads to the transcription of a plethora of target genes that promote physiological changes associated with therapeutic resistance, including the inhibition of apoptosis and senescence and the activation of drug efflux and cellular metabolism. As a result, targeting HIF-1 represents an attractive strategy to enhance the efficacy of current therapies as well as reduce resistance to chemotherapy in tumors. Approaches to inhibit HIF-1 signaling have primarily focused on reducing HIF-1-protein levels, by inducing its degradation or inhibiting its transcription, inhibiting HIF-1-mediated transcription, or disrupting the formation of the HIF-1 transcription factor complex. To date, multiple preclinical and clinical agents have been identified that effectively inhibit HIF-1 activity through various mechanisms, likely accounting for a portion of their anti-tumor efficacy. This review aims to provide an overview of our current understanding of the role of HIF-1 in therapeutic resistance and discuss the ongoing effort to develop HIF-1 inhibitors as an anti-cancer strategy.

Original languageEnglish (US)
Pages (from-to)3021-3028
Number of pages8
JournalCurrent medicinal chemistry
Volume21
Issue number26
DOIs
StatePublished - Sep 2014
Externally publishedYes

Keywords

  • HIF-1
  • Hypoxia
  • Hypoxia-inducible factor-1
  • Therapeutic resistance

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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