Carbonic Anhydrase IX: A New Drug Target for Designing Diagnostic Tools and Antitumor Agents

The tumor associated metalloenzyme carbonic anhydrase CA, EC 4.2.1.1 isozyme CA IX is highly overexpressed in many cancer types by the hypoxia inducible factor-1a HIF-1a cascade. Many hypoxic tumors overexpress CA IX and show a bad response to classical chemo- and radiotherapies. CA IX significantly contributes to acidification of the tumor environment, by catalyzing the hydration of carbon dioxide to bicarbonate and protons with its extracellularly situated active site. This leads to the acquisition of metastasic phenotypes and chemoresistance with many anticancer drugs. The report of the X-ray crystal structure of CA IX, which is a dimeric protein with a quaternary structure not evidenced earlier for this family of enzymes, allows for structure-based drug design campaigns of inhibitors against this novel antitumor target. Indeed, it has been known for some time that aromatic/heterocyclic sulfonamides and sulfamates have good affinity for this isoform, but generally they do not show specificity for the inhibition of the tumor-associated isoform versus the remaining CA isozymes CA I-VII, and XII-XV found in mammals. Inhibition of CA IX by specific and potent sulfonamide inhibitors was shown to revert the tumor acidification processes, establishing a clear-cut role of CA IX in tumorigenesis. The development of a wide range of such inhibitors belonging to diverse chemical classes sulfonamides, sulfamates, sulfamides , such as membrane-impermeant, fluorescent or metal-containing compounds, provides useful tools for highlighting the exact role of CA IX in hypoxic cancers, to control the pH im balance of tumor cells, and to develop novel diagnostic or therapeutic applications for the management of tumors. Work from several laboratories recently reported the proof-of-concept studies for the use of CA IX inhibitors as well as antibodies both in the therapy and imaging of hypoxic tumors.