title: Sulfamate inhibitor S4 influences carbonic anhydrase IX ectodomain shedding in colorectal carcinoma cells.
abstract: 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.
authors.affiliation: a Institute of Clinical Medicine, University of Oslo , Oslo , Norway .|b Department of Tumor Biology , Oslo University Hospital , Oslo , Norway .|c Department of Oncology , Akershus University Hospital , Lørenskog , Norway , and.
authors.forename: Helga Helseth
authors.initials: HH
authors.lastname: Hektoen
authors.affiliation: a Institute of Clinical Medicine, University of Oslo , Oslo , Norway .|c Department of Oncology , Akershus University Hospital , Lørenskog , Norway , and.
authors.forename: Anne Hansen
authors.initials: AH
authors.lastname: Ree
authors.affiliation: c Department of Oncology , Akershus University Hospital , Lørenskog , Norway , and.
authors.forename: Kathrine Røe
authors.initials: KR
authors.lastname: Redalen
authors.affiliation: a Institute of Clinical Medicine, University of Oslo , Oslo , Norway .|b Department of Tumor Biology , Oslo University Hospital , Oslo , Norway .|d Department of Gastroenterological Surgery , Oslo University Hospital , Oslo , Norway.
authors.forename: Kjersti
authors.initials: K
authors.lastname: Flatmark
mesh_terms: D000071231:Carbonic Anhydrase IX / Q000235:genetics / Q000378:metabolism*; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D019073:HT29 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D010671:Phenylurea Compounds / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: C575288:4-(3'-(3',5'-dimethylphenyl)ureido)phenyl sulfamate; D002257:Carbonic Anhydrase Inhibitors; D010671:Phenylurea Compounds; D013449:Sulfonamides; D000071231:Carbonic Anhydrase IX
keywords: Carbonic anhydrase IX; colorectal cancer; ectodomain shedding; extracellular pH; hypoxia; intracellular pH; sulfamate inhibitor