HIF-1 Signaling in Drug Resistance to Chemotherapy
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-1α 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.
Keywords: HIF-1, hypoxia-inducible factor-1, hypoxia, therapeutic resistance.
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