title: Bortezomib inhibits mammalian carbonic anhydrases.
abstract: We investigated the carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activity of the clinically used antitumor agent bortezomib, a marketed proteasome inhibitor, against all the catalytically active mammalian isoforms CA I-VII, IX, XII-XV. Bortezomib effectively inhibited all these CAs in the micromolar range. hCA II, the physiologically dominant cytosolic isoform showed the highest affinity for the drug, with a KIof 1.16μM. The cytosolic slow isoform hCA I was also effectively inhibited, with a KIof 1.29μM, whereas the next best affinity was observed for the membrane-anchored form mCA XV, with a KIof 2.68μM, followed by two transmembrane isoforms, hCA IX and XIV (KIs of 3.28-3.38μM). The remaining cytosolic (CA III, VII and XIII), membrane-anchored (CA IV), mitochondrial (CA VA, VB), transmembrane (CA XII) and secreted (CA VI) isoforms were slightly less inhibited by bortezomib compared to isoforms discussed above, with KIs ranging between 4.38 and 8.45μM. These data may shed some light on possible side effects and novel antitumor mechanisms of action of this drug.
authors.affiliation: Università degli Studi di Firenze, Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche e Nutraceutiche, Via U. Schiff 6, 50019 Sesto Fiorentino, Florence, Italy. Electronic address: claudiu.supuran@unifi.it.
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000069286:Bortezomib / Q000494:pharmacology*; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice
chemical_list: D000970:Antineoplastic Agents; D002257:Carbonic Anhydrase Inhibitors; D007527:Isoenzymes; D000069286:Bortezomib; D002256:Carbonic Anhydrases
keywords: Antitumor agent; Boronic acid; Carbonic anhydrase; Peptidomimetic