Carbonic Anhydrase Inhibitors: Possible Anticancer Drugs With a Novel Mechanism of Action

The tumor-associated carbonic anhydrase (CA, EC 4.2.1.1) isozyme CA IX is highly overexpressed in many cancer types via the hypoxia inducible factor-1 alpha. (HIF-1 alpha) cascade. Hypoxic tumors expressing CA IX show a poor response to classical chemo- and radio-therapy treatments. 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 to many anticancer drugs. Inhibition of CA IX by specific and potent sulfonamide inhibitors can reverse tumor acidification thus 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 approaches to manage tumor growth. Drug Dev Res 69: 297-303, 2008. (c) 2008 Wiley-Liss, Inc.