Hektoen Helga Helseth, Ree Anne Hansen, Redalen Kathrine Røe, Flatmark Kjersti
a Institute of Clinical Medicine, University of Oslo , Oslo , Norway .
b Department of Tumor Biology , Oslo University Hospital , Oslo , Norway .
J Enzyme Inhib Med Chem. 2016 Oct;31(5):779-86. doi: 10.3109/14756366.2015.1069286. Epub 2015 Aug 5.
Carbonic anhydrase IX (CAIX) is a pivotal pH regulator under hypoxia, which by its tumor-specific expression represents an attractive target for cancer therapy. Here, we report on effects of the sulfamate CAIX inhibitor S4 (4-(3'-(3″,5″-dimethylphenyl)ureido)phenyl sulfamate) in colorectal carcinoma cell lines. S4 was administered under experimental hypoxia or normoxia to HT29, KM20L2 and HCT116 cells. Effects on survival, proliferation, pH, lactate extrusion and CAIX protein expression were evaluated. S4 treatment resulted in attenuated hypoxia-induced extracellular acidification and reduced clonogenic survival under hypoxia in HT29 cells. The pH effects were present only in a [Formula: see text]-free buffer system and were accompanied by decreased lactate extrusion. The main finding of this work was that S4 treatment caused alterations in CAIX ectodomain shedding. This merits further investigation to understand how sulfamates influence CAIX activity and how such drugs may be of use in cancer treatment.
碳酸酐酶IX（CAIX）是缺氧条件下关键的pH调节剂，因其在肿瘤中的特异性表达，成为癌症治疗的一个有吸引力的靶点。在此，我们报告氨基磺酸CAIX抑制剂S4（4-(3'-(3″,5″-二甲基苯基)脲基)苯氨基磺酸）对结肠癌细胞系的影响。在实验性缺氧或常氧条件下，将S4作用于HT29、KM20L2和HCT116细胞。评估其对细胞存活、增殖、pH、乳酸外排和CAIX蛋白表达的影响。S4处理导致HT29细胞在缺氧条件下缺氧诱导的细胞外酸化减弱，克隆形成存活率降低。pH效应仅在无[化学式：见原文]缓冲系统中出现，并伴有乳酸外排减少。这项工作的主要发现是S4处理导致CAIX胞外域脱落发生改变。这值得进一步研究，以了解氨基磺酸盐如何影响CAIX活性以及这类药物在癌症治疗中的作用。
