Differential in vitro inhibitory effects of anticancer drugs on tumor-associated carbonic anhydrase isozymes CA IX and CA XII

Abstract

Carbonic anhydrase IX (CA IX) and, to a lesser extent, carbonic anhydrase XII (CA XII) are highly overexpressed in hypoxic tumors. In this study, the inhibitory effects of 11 different anticancer drugs including paclitaxel, amethopterin, etoposide, irinotecan, gemcitabine, 5-fluorouracil, oxaliplatin, epirubicin, cisplatin and carboplatin on the tumor-associated carbonic anhydrase isozymes CA IX and CA XII and cytosolic carbonic anhydrases I and II have been investigated. SX.18MV-R Applied Photophysics stopped-flow instrument was used for measuring the initial velocities for the CO2 hydration reaction catalyzed by different CA isozymes, by following the change in the absorbance of a pH indicator. CA IX and CA XII were the most affected by carboplatin and cisplatin amongst the panel of anticancer drugs. Moreover, the cytosolic carbonic anhydrases I and II can also be affected. Consequently, CA IX and CA XII are interesting targets for anticancer drug development, although more selective and powerful CA inhibitors could prove useful for elucidating the role of the protein in hypoxic cancers, for controlling the pH imbalance in tumor cells and for developing diagnostic or therapeutic applications for the management of hypoxic tumors, generally unresponsive to classical chemo- and radiotherapy.