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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 -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.
Acknowledgements
The authors thank Prof. Silvia Pastorekova for the generous gift of the CAIX antibody (M75) and Prof. Claudiu Supuran for providing the CAIX inhibitor (S4).
Declaration of interest
The authors report no declarations of interest. This work was supported by the European Union 7th Framework Programme Grant 222741-METOXIA (to A.H.R. and K.F.) and Akershus University Hospital Grant No. 2014011 (to A.H.R.). H.H.H. is Research Fellow at University of Oslo. K.R.R. is Postdoctoral Research Fellow supported by South-Eastern Norway Regional Health Authority Grant No. 2012002 (to A.H.R.).
Supplementary material available online
Supplementary Figures S1-S2