Bortezomib inhibits mammalian carbonic anhydrases

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 K_I of 1.16μM. The cytosolic slow isoform hCA I was also effectively inhibited, with a K_I of 1.29μM, whereas the next best affinity was observed for the membrane-anchored form mCA XV, with a K_I of 2.68μM, followed by two transmembrane isoforms, hCA IX and XIV (K_Is 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 K_Is 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.