Development of Inhibitors Targeting Hypoxia-Inducible Factor 1 and 2 for Cancer Therapy

Abstract

Hypoxia is frequently observed in solid tumors and also one of the major obstacles for effective cancer therapies. Cancer cells take advantage of their ability to adapt hypoxia to initiate a special transcriptional program that renders them more aggressive biological behaviors. Hypoxia-inducible factors (HIFs) are the key factors that control hypoxia-inducible pathways by regulating the expression of a vast array of genes involved in cancer progression and treatment resistance. HIFs, mainly HIF-1 and -2, have become potential targets for developing novel cancer therapeutics. This article reviews the updated information in tumor HIF pathways, particularly recent advances in the development of HIF inhibitors. These inhibitors interfere with mRNA expression, protein synthesis, protein degradation and dimerization, DNA binding and transcriptional activity of HIF-1 and -2, or both. Despite efforts in the past two decades, no agents directly inhibiting HIFs have been approved for treating cancer patients. By analyzing results of the published reports, we put the perspectives at the end of the article. The therapeutic efficacy of HIF inhibitors may be improved if more efforts are devoted on developing agents that are able to simultaneously target HIF-1 and -2, increasing the penetrating capacity of HIF inhibitors, and selecting suitable patient subpopulations for clinical trials.

Keywords: Hypoxia-inducible factor; anti-cancer drug; cancer; clinical trials.

Fig. 1. The HIF pathways and potential interfering points. Interfering points: a, HIFα mRNA; b, protein synthesis; c, protein stability and degradation; d, dimerization; e, DNA binding; f, transcriptional activity; g, Nuclear translocation. ARNT, aryl hydrocarbon receptor nuclear translocator (also called HIF-1α); GFs, growth factors; HIF, hypoxia-inducible factor; HREs, hypoxia-response elements; Hsp90, heat shock protein 90; PHD, prolyl hydroxylase; Ub, Ubiquitin; pVHL, von Hippel-Lindau tumor protein; HDAC, histone deacetylase; CBP, CREB-binding protein.

Fig. 2. Representative HIF-targeted genes and their roles in cancer progression and therapy resistance. ALDA, aldolase A; ALDC, aldolase C; ADM, adrenomedullin; ABCG2, ATP-binding cassette sub-family G member 2; CATHD, cathepsin D; CCL, chemokine (C-C motif) ligand; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; CXCL, chemokine (C-X-C motif) ligand; ENG, endoglin; ET1, endothelin-1; FN1, fibronectin 1; FOXP3, forkhead box P3; GAPDH, glyceraldehyde-3-P-dehydrogenase; GITR, glucocorticoid-induced TNFR-related protein; GLUT, glucose transporter; HK, hexokinase; HIF, hypoxia-inducible factor; HLA-G, human leukocyte antigen G; IGF2, insulin-like growth factor 2; IGF-BP, insulin-like growth factor binding protein; LDHA, lactate dehydrogenase A; LRP1, LDL-receptor-related protein 1; MDR1, multidrug resistance 1; MMP2, matrix metal-loproteinase 2; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NOS2, nitric oxide synthase 2; OCT4, octamer-binding transcription factor 4; PD-L1, programmed death-ligand 1; PFKBF3, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-3; PFKL, 6-phosphofructokinase, liver type; PGK1, phosphoglycerate kinase 1; PKM, pyruvate kinase M; TGF, transforming growth factor; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor.