Hypoxia inducible factor pathway inhibitors as anticancer therapeutics

Abstract

Hypoxia is a significant feature of solid tumor cancers. Hypoxia leads to a more malignant phenotype that is resistant to chemotherapy and radiation, is more invasive and has greater metastatic potential. Hypoxia activates the hypoxia inducible factor (HIF) pathway, which mediates the biological effects of hypoxia in tissues. The HIF complex acts as a transcription factor for many genes that increase tumor survival and proliferation. To date, many HIF pathway inhibitors indirectly affect HIF but there have been no clinically approved direct HIF inhibitors. This can be attributed to the complexity of the HIF pathway, as well as to the challenges of inhibiting protein-protein interactions.

Figure 1. The hypoxia inducible factor-1

Under normoxic conditions, HIF-1α is rapidly hydroxylated by prolyl hydroxylases, which mediates binding by the VHL ubiquitin ligase complex, addition of poly-Ub which tags it for proteosomal degradation. Under hypoxic conditions, prolyl hydroxylases cannot hydroxylate HIF-1α, preventing VHL binding which leads to HIF-1α stabilization. HIF-1α then heterodimerizes with HIF-1β, recruits the p3oo/CBP co-factors and forms an active HIF transcription complex in the nucleus that binds to HREs on target genes and activates their transcription. HIF: Hypoxia inducible factor; HRE: Hypoxia response element; Ub: Ubiquitin chains; VHL: von Hippel-Lindau tumor suppressor protein.

Figure 2. Mechanisms of hypoxia inducible factor inhibition

HIF: Hypoxia inducible factor; HRE: Hypoxia response element; PHD: Prolyl hydroxylases; Ub: Ubiquitin chains; VHL: von Hippel-Lindau tumor suppressor protein.

Figure 3. Trends of hypoxia inducible factor inhibitors from 2000–2012

(A) Number of patent issued by year. (B) Number of publications by year. (C) Number of clinical trials by year. (D) Number of citations by year. Data taken from [308-310].