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Hypoxia-inducible factor (HIF) mediates multiple intracellular processes that drive cellular metabolism and induce proliferation. Dysregulated HIF expression is associated with oncogenic cellular transformation. Moreover, high HIF levels correlate with tumor aggressiveness and chemoresistance, indicating the vital effect of HIF-1α on tumorigenicity. Currently, widespread in-vitro and in-vivo research is focusing on targeting HIF with drugs that have already been approved for use by the FDA, such as belzutifan, in renal cell carcinoma. HIF inhibition is mostly associated with tumor size reduction; however, drug toxicity remains a challenge. In this review, we focus on the potential of targeting HIF in prostate cancer (PC) and summarize the scientific background of HIF activity in PC. This finding emphasizes the rationale for using HIF as a therapeutic target in this malignancy. We have listed known HIF inhibitors that are being investigated in preclinical studies and their potential as anticancer drugs for PC. Although HIF-targeting agents have been investigated for over a decade, their use in therapy-resistant cancers remains relevant and should be explored further. In addition, the use of naturally occurring HIF inhibitors should be considered as an add-on therapy for the currently used regimens.

Targeting HIF-1 for prostate cancer: a synthesis of preclinical evidence