Li Weidong, Sun Xueying
The Hepatosplenic Surgery Center, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Harbin 150001, China.
Department of Molecular Medicine & Pathology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland 1142, New Zealand.
Recent Pat Anticancer Drug Discov. 2018;13(4):455-468. doi: 10.2174/1574892813666180831102519.
Solid tumors often contain hypoxic microenvironments due to abnormal vasculatures and outweighing demands of oxygen. Cancer cells rely on anaerobic respiration, leading to sequential acidic microenvironments. Hypoxic and acidic microenvironments cause genetic instability and activate signaling pathways, contributing to cancer progression and therapy resistance, and have become targets for developing novel anti-cancer agents.
This article reviews recent advances in the development of novel anti-cancer drugs targeting hypoxic and acidic microenvironments.
Recent patents and published literature related to anti-cancer agents targeting tumor hypoxic and acidic microenvironments were searched and reviewed. Key termed used in the searching included cancer, anti-cancer drug, neoplasm, clinical trials, tumor microenvironment, hypoxic microenvironment, acidic microenvironment, hypoxia-inducible factors, hypoxia; metabolism; Warburg effect and aerobic glycolysis.
A number of Hypoxia-Inducible Factor (HIF) inhibitors have been developed or discovered, but most of them have only exhibited indirect effects on HIFs, and a limited number of drugs are able to directly interfere with mRNA and protein of HIFs, the dimerization of α and β subunits, or the interaction between HIFs and its activators. The development of agents targeting acidic microenvironments focuses on V-ATPase, monocarboxylic acid transporters, Na+/H+ exchangers and carbonic anhydrases. Proton pump inhibitors as V-ATPase inhibitors have been applied in treating various tumors as an adjuvant therapy, but none of the other inhibitors has been approved for cancer treatment.
Developing more specific agents, and seeking sensitive, applicable and accurate biomarkers may improve the efficacy of drugs targeting hypoxic and acidic microenvironments.
由于血管异常和氧气需求过高，实体瘤常含有缺氧微环境。癌细胞依赖无氧呼吸，导致相继出现酸性微环境。缺氧和酸性微环境会导致基因不稳定并激活信号通路，促进癌症进展和治疗耐药性，已成为开发新型抗癌药物的靶点。
本文综述了针对缺氧和酸性微环境的新型抗癌药物研发的最新进展。
检索并综述了与靶向肿瘤缺氧和酸性微环境的抗癌药物相关的近期专利和已发表文献。检索中使用的关键词包括癌症、抗癌药物、肿瘤、临床试验、肿瘤微环境、缺氧微环境、酸性微环境、缺氧诱导因子、缺氧；代谢；瓦伯格效应和有氧糖酵解。
已经开发或发现了多种缺氧诱导因子（HIF）抑制剂，但其中大多数仅对HIFs表现出间接作用，只有少数药物能够直接干扰HIFs的mRNA和蛋白质、α和β亚基的二聚化或HIFs与其激活剂之间的相互作用。针对酸性微环境的药物研发主要集中在V-ATP酶、单羧酸转运蛋白、Na+/H+交换体和碳酸酐酶。质子泵抑制剂作为V-ATP酶抑制剂已作为辅助疗法应用于多种肿瘤的治疗，但其他抑制剂均未获批用于癌症治疗。
开发更具特异性的药物，并寻找敏感、适用且准确的生物标志物，可能会提高针对缺氧和酸性微环境的药物疗效。
