Selective inhibition of human carbonic anhydrase IX in Xenopus oocytes and MDA-MB-231 breast cancer cells

Abstract

Human carbonic anhydrase IX (CA IX) is overexpressed in the most aggressive and invasive tumors. Therefore, CA IX has become the promising antitumor drug target. Three inhibitors have been shown to selectively and with picomolar affinity inhibit human recombinant CA IX. Their inhibitory potencies were determined for the CA IX, CA II, CA IV and CA XII in Xenopus oocytes and MDA-MB-231 cancer cells. The inhibition IC₅₀ value of microelectrode-monitored intracellular and extracellular acidification reached 15 nM for CA IX, but with no effect on CA II expressed in Xenopus oocytes. Results were confirmed by mass spectrometric gas analysis of lysed oocytes, when an inhibitory effect on CA IX catalytic activity was found after the injection of 1 nM VD11-4-2. Moreover, VD11-4-2 inhibited CA activity in MDA-MB-231 cancer cells at nanomolar concentrations. This combination of high selectivity and potency renders VD11-4-2, an auspicious therapeutic drug for target-specific tumor therapy.

Keywords:

• Benzenesulfonamides
• carbonic anhydrase IX
• MDA-MB-231 cells
• Xenopus oocytes

Acknowledgements

We thank Hans-Peter Schneider and Sina Ibne Noor for their skillful assistance with the experiments and experimental data analysis.

Declaration of interest

The authors have no competing interests. This research was funded by the grant [No. TAP LLT-1/2016] from the Research Council of Lithuania.

Supplementary materials available online