Ways into Understanding HIF Inhibition

Abstract

Hypoxia is a key characteristic of tumor tissue. Cancer cells adapt to low oxygen by activating hypoxia-inducible factors (HIFs), ensuring their survival and continued growth despite this hostile environment. Therefore, the inhibition of HIFs and their target genes is a promising and emerging field of cancer research. Several drug candidates target protein–protein interactions or transcription mechanisms of the HIF pathway in order to interfere with activation of this pathway, which is deregulated in a wide range of solid and liquid cancers. Although some inhibitors are already in clinical trials, open questions remain with respect to their modes of action. New imaging technologies using luminescent and fluorescent methods or nanobodies to complement widely used approaches such as chromatin immunoprecipitation may help to answer some of these questions. In this review, we aim to summarize current inhibitor classes targeting the HIF pathway and to provide an overview of in vitro and in vivo techniques that could improve the understanding of inhibitor mechanisms. Unravelling the distinct principles regarding how inhibitors work is an indispensable step for efficient clinical applications and safety of anticancer compounds.

Cancer Cell Metabolism in Hypoxia: Role of HIF-1 as Key Regulator and Therapeutic Target

“…Below, we briefly report the main aspects of the inhibition strategy and examples of chemical agents used. For a more detailed discussion about drugs, targets, and mechanisms, more specific reviews should be consulted [ 121 , 122 , 123 ].…”

Exploring hypoxic biology to improve radiotherapy outcomes

“…Several compounds have been studied as inhibitors of HIF- α transcription, translation, and protein stabilisation (Ref. 116). Of these, some, such as SN-38 (the active metabolite of irinotecan), alongside its well-established radiosensitiser effect as a topoisomerase I inhibitor, can also lead to increased radiosensitivity through inhibiting radiation-induced HIF-1 α in colorectal cancer (Ref.…”

“…PX-478 decreases HIF-1 α levels by inhibiting HIF-1 α translation, as well as inhibiting de-ubiquitination leading to HIF-1 α protein degradation (Ref. 116). Palayoor et al have shown a potential role for PX-478 as a clinical radiation enhancer in prostate carcinoma cells (Ref.…”

Prevention of Post-Operative Adhesions: A Comprehensive Review of Present and Emerging Strategies

“…The potential for the development of adverse and unanticipated effects is high due to the intertwined nature. Regarding HIF inhibitors, the use of many is dampened by their off-target effects, affecting different pathways in DNA replication, cell division, or cell signaling [220]. HMG-CoA reductase inhibitors have been hypothesized to influence intracellular signaling pathways and immune processes [221,222]; their several pleiotropic off-target effects have been investigated in cancer therapy by delaying DNA repair and inducing senescence [223].…”