Specific inhibition of carbonic anhydrase IX activity enhances the in vivo therapeutic effect of tumor irradiation

Abstract

Specific inhibition of CAIX activity enhanced the effect of tumor irradiation and might, therefore, be an attractive strategy to improve overall cancer treatment.

Sulfamate inhibitor S4 influences carbonic anhydrase IX ectodomain shedding in colorectal carcinoma cells

“…In order for CAIX to catalyze CO 2 =HCO À 3 , the reaction must be driven out of equilibrium, hence in a perfectly balanced system its role becomes redundant, which might explain why S4 did not influence CAIX activity under CO 2 =HCO À 3 -buffered conditions 25 . Although the role of the buffer system was relatively clear in our experiments, varying results have been obtained by others, which illustrate the experimental complexity and underline the importance of controlling the experimental conditions 11,12,26 . Hypoxia creates a shift in metabolism toward glycolysis, where the final product is lactic acid 27 .…”

“…Interestingly, S4 treatment reduced hypoxia-induced lactate accumulation in the media, suggesting that S4 inhibited CAIX-dependent extrusion of lactic acid. However, there have also been reports showing that lactate extrusion can be independent of CAIX expression levels, thus S4 might influence this process through a CAIX-independent mechanism 11,26 . S4 has previously shown to inhibit cell proliferation in colorectal and breast cancer models in vitro, both under normoxic and hypoxic conditions 22,31 .…”

Carbonic anhydrase IX correlates with survival and is a potential therapeutic target for neuroblastoma

“…Further in vitro studies are necessary to shed light on the mechanisms of suppression of tumor proliferation by various CAIX inhibitors. Xenograft tumor model studies have shown that the use of CAIX inhibiting sulfonamides is feasible in vivo, which constitutes an important step towards clinical applicability 36,37 . There are also preclinical and clinical trials on the way to establish biological inhibitors for CAIX [38][39][40] .…”

7-Aryl-triazolyl-substituted sulfocoumarins are potent, selective inhibitors of the tumor-associated carbonic anhydrase IX and XII

“…Sulfocoumarins 7-14 were screened in vitro for the inhibition against four physiologically relevant hCA isoforms, the cytosolic hCAI and II and the trans-membrane tumor-associated hCA IX and XII 10,12,24,[57][58][59][60] . Table 1 shows the inhibition data obtained and compared to the standard clinically used sulfonamide acetazolamide (AAZ) after a period of incubation of 6 h of the enzyme and inhibitors.…”