Ways into Understanding HIF Inhibition

SIMPLE SUMMARY: Cancer cells adapt to hypoxia, survive, and grow. To that aim, they engage hypoxia-inducible pathways. These pathways are under intense investigation in search of new therapies to interfere with signaling components to kill cancer cells. Nowadays, new technologies enable more in-depth studies of hypoxia-induced signaling including protein–protein interaction and transcriptional processes, as well as the mode of action of different inhibitors. In this review, we give insight into useful techniques for studying the components of the hypoxia-inducible pathway and current inhibitors. 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.