Targeting hypoxia-inducible factor-1, for cancer treatment: Recent advances in developing small-molecule inhibitors from natural compounds

Rapid progress in molecular cancer biology coupled with the discovery of novel oncology drugs has opened new horizons for cancer target discovery. As one of the crucial signaling pathways related to tumorigenesis, hypoxiainducible factor-1 (HIF-1) coordinates the activity of many transcription factors and their downstream molecules that impact tumor growth and metastasis. Accumulating evidence suggests that the transcriptional responses to acute hypoxia are mainly attributable to HIF-1 alpha. Moreover, the overexpression of HIF-1 alpha in several solid cancers has been found to be strongly associated with poor prognosis. Thus, pharmacological targeting of the HIF-1 signaling pathways has been considered as a new strategy for cancer therapy in the recent years. Although over the past decade, tremendous efforts have been made in preclinical studies to develop new HIF-1 inhibitors from natural products (reservoirs of novel therapeutic agents), to date, these efforts have not been successfully translated into clinically available treatments. In this review, we provide new insights into the biopharmacological considerations for selecting natural compounds as potential HIF-1 inhibitors to accelerate anti-cancer drug development. In addition, we highlighted the importance of assessing the dependency of cancer on HIF1A to shortlist cancer types as suitable disease models. This may subsequently lead to new paradigms for discovering more HIF-1 inhibitors derived from natural products and facilitate the development of potent therapeutic agents targeting specific cancer types.

Automated summary

Rapid progress in molecular cancer biology and the discovery of new oncology drugs have opened new opportunities for cancer target discovery. HIF-1, a crucial signaling pathway related to tumorigenesis, regulates the activity of many transcription factors and downstream molecules that affect tumor growth and metastasis. Overexpression of HIF-1 alpha is strongly associated with poor prognosis in several solid cancers. Pharmacological targeting of the HIF-1 signaling pathway has been considered a new strategy for cancer therapy, but translation into clinically available treatments remains challenging.