Clottes Eric
Institut de pharmacologie et de biologie structurale, 205, route de Narbonne, 31077 Toulouse Cedex 4.
Bull Cancer. 2005 Feb;92(2):119-27.
Hypoxia-inducible factor-1 is a heterodimer made up of an oxygen-regulated HIF1alpha subunit and a constitutively expressed HIF1beta subunit. Among the 70 target genes of HIF-1 known so far, several are involved in angiogenesis, erythropoiesis, cell proliferation, cell viability, and glucose and iron metabolisms. Intratumoral hypoxia or genetic alterations can lead to HIF-1 alpha over-expression. HIF-1 over-expression has been associated with an increased patient mortality rate in many cancer types. Also, in vitro suppression of hif1alpha gene expression has been shown to be efficient in tumour growth repression. During the past five years, drugs able to indirectly inhibit HIF1 activity have been rationally or empirically developed. Some are currently evaluated in clinical trials, but further work has still to be undertaken to rationally identify new specific inhibitors of HIF1 and to test their efficacy as anticancer therapeutics. This review focuses on HIF1 regulation, HIF1 involvement in tumour promotion, the different HIF-1 inhibitors currently tested and their mechanisms of action.
缺氧诱导因子-1是一种异源二聚体，由一个受氧调节的HIF1α亚基和一个组成型表达的HIF1β亚基组成。在目前已知的HIF-1的70个靶基因中，有几个参与血管生成、红细胞生成、细胞增殖、细胞活力以及葡萄糖和铁代谢。肿瘤内缺氧或基因改变可导致HIF-1α过度表达。在许多癌症类型中，HIF-1过度表达与患者死亡率增加相关。此外，体外抑制hif1α基因表达已被证明在抑制肿瘤生长方面有效。在过去五年中，已合理或经验性地开发出能够间接抑制HIF1活性的药物。一些药物目前正在进行临床试验，但仍需进一步开展工作，以合理鉴定新的HIF1特异性抑制剂，并测试其作为抗癌治疗药物的疗效。本综述重点关注HIF1调节、HIF1在肿瘤促进中的作用、目前正在测试的不同HIF-1抑制剂及其作用机制。
