Ajith Thekkuttuparambil A
Professor Biochemistry, Department of Biochemistry, Amala Institute of Medical Sciences, Amala Nagar, Thrissur-680 555, Kerala, India.
J Basic Clin Physiol Pharmacol. 2018 Dec 19;30(1):11-18. doi: 10.1515/jbcpp-2017-0167.
Hypoxia-inducible factors (HIFs) are transcription factors that are expressed in the hypoxic tumor microenvironment. They are involved in the cellular adaptations by improving the metabolism of glucose and enhance the expression of vascular endothelial growth factor, platelet-derived growth factor and angiopoietin, thereby they play a pivotal role in the angiogenesis. Hypoxia can increase the expression of nuclear factor-kappa B which promotes the pro-inflammatory status. Abnormally high angiogenesis, inflammation, antiapoptosis and anaerobic glycolysis can augment the progression and metastasis of tumor. Hence, HIFs remain one of the promising antiangiogenic agents as well as a direct target for interfering with the energetic of cancer cells in order to regulate the tumor growth. Previous studies found agents like topotecan, acriflavine and benzophenone-1B etc. to block the HIF-α mediated angiogenesis. The effect is mediated through interfering any one of the processes in the activation of HIF such as nuclear translocation of HIF-1α; dimerization of HIF-1α with β in the nucleus; HIF-1α/HIF-2α mediated induction of VEGF or translation of HIF-1α mRNA. Despite the experimental studies on the inhibitory molecules of HIFs, none of them are available for the clinical use. This review article discusses the recent update on the HIF-targeted therapy in cancer.
缺氧诱导因子（HIFs）是在缺氧肿瘤微环境中表达的转录因子。它们通过改善葡萄糖代谢参与细胞适应过程，并增强血管内皮生长因子、血小板衍生生长因子和血管生成素的表达，从而在血管生成中发挥关键作用。缺氧可增加促进促炎状态的核因子-κB的表达。异常高的血管生成、炎症、抗凋亡和无氧糖酵解可促进肿瘤的进展和转移。因此，HIFs仍然是有前景的抗血管生成药物之一，也是干扰癌细胞能量代谢以调节肿瘤生长的直接靶点。先前的研究发现拓扑替康、吖啶黄素和二苯甲酮-1B等药物可阻断HIF-α介导的血管生成。其作用是通过干扰HIF激活过程中的任何一个过程来介导的，如HIF-1α的核转位；HIF-1α在细胞核中与β的二聚化；HIF-1α/HIF-2α介导的VEGF诱导或HIF-1α mRNA的翻译。尽管对HIFs的抑制分子进行了实验研究，但它们都尚未用于临床。这篇综述文章讨论了癌症中HIF靶向治疗的最新进展。
