Targeting tumor-associated carbonic anhydrase IX in cancer therapy

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.tips.2006.09.002 Byline: Anne Thiry (1), Jean-Michel Dogne (1), Bernard Masereel (1), Claudiu T. Supuran (2) Abstract: Carbonic anhydrase isoform IX (CA IX) is highly overexpressed in many types of cancer. Its expression, which is regulated by the HIF-1 transcription factor, is strongly induced by hypoxia and correlates with a poor response to classical chemo- and radiotherapies. CA IX contributes to acidification of the tumor environment by efficiently catalyzing the hydration of carbon dioxide to bicarbonate and protons, thereby leading to acquisition of metastasic phenotypes and chemoresistance to weakly basic anticancer drugs. Inhibition of this enzymatic activity by specific inhibitors, such as the sulfonamide indisulam, reverts these processes, establishing a clear-cut role for CA IX in tumorigenesis. Thus, selective CA IX inhibitors could prove useful for elucidating the role of CA IX in hypoxic cancers, for controlling the pH imbalance in tumor cells and for developing diagnostic or therapeutic applications for tumor management. Indeed, fluorescent inhibitors and membrane-impermeant sulfonamides have recently been used as proof-of-concept tools, demonstrating that CA IX is an interesting target for anticancer drug development. Author Affiliation: (1) Drug Design and Discovery Center, University of Namur, 61 rue de Bruxelles, B-5000 Namur, Belgium (2) Polo Scientifico, Laboratorio di Chimica Bioinorganica, Room 188, Universita degli Studi di Firenze, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy