Targeting tumor-associated carbonic anhydrase IX in cancer therapy.
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 metastatic 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.
Thiry
Anne
A
Drug Design and Discovery Center, University of Namur, 61 rue de Bruxelles, B-5000 Namur, Belgium.
Dogné
Jean-Michel
JM
Masereel
Bernard
B
Supuran
Claudiu T
CT
D000818:Animals; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D002256:Carbonic Anhydrases / Q000737:chemistry / Q000378:metabolism*; D020134:Catalytic Domain; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm; D006801:Humans; D006863:Hydrogen-Ion Concentration; D000860:Hypoxia / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D011487:Protein Conformation; D013449:Sulfonamides / Q000627:therapeutic use
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D002257:Carbonic Anhydrase Inhibitors; C439829:N-(3-chloro-7-indolyl)-1,4-benzenedisulphonamide; D013449:Sulfonamides; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases