Cancer Therapeutic Agents Targeting Hypoxia-Inducible Factor-1

Abstract

The discovery of hypoxia-inducible factor-1 has led to a rapidly increasing understanding of the molecular mechanism of tumor hypoxia in the past two decades. Today it is generally accepted that HIF-1 plays a pivotal role in the cellular response to tumor hypoxia which represents a major obstacle to the success of radiotherapy and chemotherapy. Meanwhile, many details involved in the expression, accumulation and transactivation of HIF-1 have been well elucidated. Targeting HIF-1 has become a novel and efficient strategy for cancer therapy and a number of agents have been developed aiming to suppress HIF-1. This review will concisely introduce the general knowledge on the molecular biology of HIF-1 and possible targets along the HIF-1 pathway. Moreover, a number of compounds reported with anti-HIF-1 activity are included and mainly classified as direct and indirect inhibitors based on their different modes of action. While direct HIF-1 inhibitors prevent HIF-1 from transactivation, DNA binding and subsequently initiating transcriptional activity, indirect HIF-1 inhibitors generally block the transcription or translation of HIF-1α or promote the degradation of HIF-1α protein. According to different structural features, direct HIF-1 inhibitors are divided into several groups: polyamides, quinols and naphthoquinone spiroketal analogues, shikonin derivatives, epidithiodiketopiperazines, and two representative drugs: echinomycin and bortezomib. In the same way, indirect inhibitors comprise the following classes: polyphenols, benzoazaheterocycles, rapamycins, camptothecins, geldanamycins, (aryloxyacetylamino)benzoic acid analogues, 2-methoxyestradiol and analogues, hydroxamic acid compounds and others. The rest with mechanism still not so clear would also be listed and introduced, with an emphasis on the marinederived natural products. The in vitro and/or in vivo activities of these compounds and their mechanisms of HIF-1 inhibition would be discussed and the SARs of unique structural types of HIF-1 inhibitors will be briefly concluded.

Targeting hypoxia signalling for the treatment of ischaemic and inflammatory diseases

“…Original studies by Kong et al 149 screened the National Cancer Institute small-molecule library and discovered that echinomycin (NSC-13502) potently inhibited HIF1 binding to its cognate HRE. Accordingly, echinomycin has been profiled among a number of direct and indirect HIF1 target drugs that show more or less promise as cancer therapeutics 150 (TABLE 1). More recently, it was shown that cardiac glycosides inhibit HIF 13 .…”

Biosynthetic Modularity Rules in the Bisintercalator Family of Antitumor Compounds

“…These HREs are placed in eukaryotic promoters which control genes involved in cellular survival, glycolysis, angiogenesis, migration and cellular invasion of cancer cells. HREs are very important targets for cancer therapy [108,109,110]. HRE are also important in non-tumor cell processes, as during heterotopic bone formation (after surgery or trauma), which depends also on hypoxia.…”

Role of VHL gene mutation in human renal cell carcinoma

“…There are a number of compounds reported with anti-HIF-1 activity and are mainly classified as direct and indirect inhibitors based on their different modes of action. While direct HIF-1 inhibitors prevent HIF-1 from transactivation, DNA binding, and subsequently initiating transcriptional activity, indirect HIF-1 inhibitors generally block the transcription or translation of HIF-1α or promote the degradation of HIF-1α protein [65]. According to different structural features, direct HIF-1 inhibitors are divided into several groups: polyamides, quinols and naphthoquinone spiroketal analogs, shikonin derivatives, epidithiodiketopiperazines, and two representative drugs echinomycin and bortezomib.…”