Cancer Therapeutic Agents Targeting Hypoxia-Inducible Factor-1

R.      Wang; S.      Zhou; S.      Li

doi:10.2174/092986711796391606

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.

Keywords: Camptothecins, direct inhibitors, geldanamycins, HIF-1 inhibitors, hypoxia, hypoxia-inducible factor-1, indirect inhibitors, mechanism, 2-methoxyestradiol, polyamides, polyphenols, rapamycins, SARs, shikonin derivatives