Carbonic anhydrase IX: A new druggable target for the design of antitumor agents

Abstract

Carbonic anhydrases (CAs, EC 4.2.1.1) are a family of enzymes widespread in all life kingdoms. In mammals, isozyme CA IX is highly overexpressed in many cancer types being present in few normal tissues. Its expression is strongly induced by hypoxia present in many tumors, being regulated by the HIF transcription factor and correlated with a poor response to classical chemo- and radiotherapies. CA IX was recently shown to contribute to acidification of the tumor environment, by efficiently catalyzing the hydration of carbon dioxide to bicarbonate and protons with its extracellularly situated active site, leading both to the acquisition of metastasic phenotypes and to chemoresistance with weakly basic anticancer drugs. Inhibition of this enzymatic activity by specific and potent inhibitors was shown to revert these acidification processes, establishing a clear-cut role of CA IX in tumorigenesis. The development of a wide range of potent and selective CA IX inhibitors belonging to diverse chemical classes, such as membrane-impermeant, fluorescent or metal-containing such agents, could thus provide 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. Indeed, both fluorescent inhibitors or positively charged, membrane impermeant sulfonamides have been recently developed as potent CA IX inhibitors and used as proof-of-concept tools for demonstrating that CA IX constitutes a novel and interesting target for the anticancer drug development.

Sulfapyridine-like benzenesulfonamide derivatives as inhibitors of carbonic anhydrase isoenzymes I, II and VI

“…Among the sixteen 16 isoenzymes, described up to now, CAI and CAII are present at high concentrations in the cytosol in erythrocytes, and CAII has the highest turnover rate of all the CAs [1][2][3][4][5][6][7][8] . Carbonic anhydrase VI (CA VI) is a secretory enzyme that was initially described in the ovine parotid gland, saliva and normal human serum 8 .…”

Endostar enhances the antitumor effects of radiation by affecting energy metabolism and alleviating the tumor microenvironment in a Lewis lung carcinoma mouse model

“…In cancer cells, HIF-1α induces the expression and enhances the activity of several glycolytic proteins that differ from those detected in nonmalignant cells, including transporters (glucose transporters 1 and 3) and enzymes (hexokinase I and II, and phosphofructokinase-L) (15 anhydrase IX (CA IX) contributes to the acidification of the tumor environment by efficiently catalyzing the hydration of carbon dioxide to bicarbonate and protons with its extracellularly situated active site. CA IX expression is strongly induced by hypoxia, which is present in numerous tumors and regulated by the transcription factor, HIF (16). The present study hypothesized that the antitumor effect of the antigenic agent, Endostar, in combination with radiotherapy was associated with glycolysis and changes of tumor environment pH.…”

Carbonic Anhydrases inhibitory effects of new benzenesulfonamides synthesized by using superacid chemistry

“…Sixteen different α-carbonic anhydrase isoforms have been isolated and characterized in mammals and many of them are well established therapeutic targets to treat a wide range of disorders [1][2][3][4] . Although inhibition of α-carbonic anhydrases (α-CAs) by aromatic and heterocyclic sulfonamides has been largely studied for 50 years with applications in the treatment of various diseases [5][6][7] , this class of compounds remains an attractive chemical family in the design of new inhibitors, as shown by the ongoing research in this field [8][9][10][11][12] .…”