Current insights and future perspectives of hypoxia-inducible factor-targeted therapy in cancer

Abstract

Hypoxia-inducible factors (HIFs) are transcription factors that are expressed in the hypoxic tumor microenvironment. They are involved in the cellular adaptations by improving the metabolism of glucose and enhance the expression of vascular endothelial growth factor, platelet-derived growth factor and angiopoietin, thereby they play a pivotal role in the angiogenesis. Hypoxia can increase the expression of nuclear factor-kappa B which promotes the pro-inflammatory status. Abnormally high angiogenesis, inflammation, antiapoptosis and anaerobic glycolysis can augment the progression and metastasis of tumor. Hence, HIFs remain one of the promising antiangiogenic agents as well as a direct target for interfering with the energetic of cancer cells in order to regulate the tumor growth. Previous studies found agents like topotecan, acriflavine and benzophenone-1B etc. to block the HIF-α mediated angiogenesis. The effect is mediated through interfering any one of the processes in the activation of HIF such as nuclear translocation of HIF-1α; dimerization of HIF-1α with β in the nucleus; HIF-1α/HIF-2α mediated induction of VEGF or translation of HIF-1α mRNA. Despite the experimental studies on the inhibitory molecules of HIFs, none of them are available for the clinical use. This review article discusses the recent update on the HIF-targeted therapy in cancer.

Keywords: angiogenesis; apoptosis; clear cell renal cell carcinoma; hypoxia; hypoxia-inducible factor; normoxia; nuclear factor-kappa B.