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.

Autocrine VEGF signalling on M2 macrophages regulates PD‐L1 expression for immunomodulation of T cells

“…We not only construct the actual trilateral relations among M2 macrophages, autocrine VEGF and PD‐L1 expression for their role of immunomodulation, but also support a theory in biological aspect to explain how anti‐VEGF signalling turns to be a main character to enhance the effect of PD‐1 blockade in cancer therapy. Additionally, it highlights the value for the development of inhibitors targeting hypoxia‐inducible factor 1 and 2 in TAMs . Further investigation is needed to examine whether PD‐L1 + M2 macrophages stimulated by autocrine VEGF can be potent for immunotherapy of autoimmune diseases.…”

“…Additionally, it highlights the value for the development of inhibitors targeting hypoxia-inducible factor 1 and 2 in TAMs. 35 Further investigation is needed to examine whether PD-L1 + M2 macrophages stimulated by autocrine VEGF can be potent for immunotherapy of autoimmune diseases.…”

HIF1α Signaling in the Endogenous Protective Responses after Neonatal Brain Hypoxia-Ischemia

“…2ME2 is an endogenous metabolite of estradiol and is the most commonly employed HIF1α inhibitor. The mechanism for its inhibition on HIF1α in a human tumor cell line and in human umbilical vein endothelial cells is that 2ME2 inhibits HIF1α mRNA translation/de novo synthesis, and its association with microtubules, thereby blocking HIF1 nuclear accumulation and its transcriptional activity [39][40][41]. In the adult rodent brain, administration of 2ME2 before or soon after insult protected against global ischemia [42] or middle cerebral artery occlusion (MCAO)-induced brain damage [43,44], although 1 study reported that 2ME2 given 10 min after ischemia exacerbated apoptotic death in the CA1 region of the hippocampus following global ischemia [45].…”

Crosstalk between hydroxytyrosol, a major olive oil phenol, and HIF-1 in MCF-7 breast cancer cells

“…The data we present appear to indicate that, in a hypoxic context, HT modulates different molecular mechanisms involved in tumor malignancy and resistance to therapy. The inhibition of the PI3K/Akt/mTOR pathway can overcome resistance to hormonal and anti-HER2 targeted therapies 83 , and HIF inhibitors are also promising molecules in cancer treatment 84 . Therefore, our data support that HT could have a chemomodulatory effect in breast cancer.…”