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.
Highlights
The changes in pH regulation and altered cellular metabolism are key features of solid tumors
Results were confirmed by mass spectrometric gas analysis of lysed oocytes, when an inhibitory effect on carbonic anhydrase IX (CA IX) catalytic activity was found after the injection of 1 nM VD11-4-2
The inhibitory potency of VD11-4-2 against Carbonic anhydrase (CA) IX and CA II was determined by measuring the rate of rise in intracellular [H+] (D[H+]i/Dt) during repeated application of CO2/HCO3À
Summary
The changes in pH regulation and altered cellular metabolism are key features of solid tumors. Due to inadequate blood supply, metabolism in tumor cells is highly affected by expression of many hypoxia-inducible genes. Changes in metabolic pathways occur to survive hypoxic conditions. Known as ‘‘Warburg effect’’1,2, extensive glycolysis leads to tremendous amounts of lactate and protons, which significantly contribute to acidification of extracellular space. The active transport for removing H+ from the cell is mediated by H+ATPase pumps and secondary active Na+/H+ exchangers (NHE), or affected by HCO3À influx via Na+-HCO3À co-transporters (NBC) or Na+-dependent ClÀ/HCO3À exchangers (NDAE)[5,6,7,8,9]. Hypoxic and acidic microenvironment promotes the breakdown of extracellular matrix[10] and allows tumor progression
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