Assessment of the antiproliferative and apoptotic roles of sulfonamide carbonic anhydrase IX inhibitors in HeLa cancer cell line

Abstract

Carbonic anhydrase IX (CA IX) has recently been validated as an antitumor/antimetastatic drug target. In this study, we examined the underlying molecular mechanisms and the anticancer activity of sulfonamide CA IX inhibitors against cervical cancer cell lines. The effects of several sulfonamides on HeLa, MDA-MB-231, HT-29 cancer cell lines, and normal cell lines (HEK-293, PNT-1A) viability were determined. The compounds showed high cytotoxic and apoptotic activities, mainly against HeLa cells overexpressing CA IX. We were also examined for intracellular reactive oxygen species (ROS) production; intra-/extracellular pH changes, for inhibition of cell proliferation, cellular mitochondrial membrane potential change and for the detection of caspase 3, 8, 9, and CA IX protein levels. Of the investigated sulfonamides, one compound was found to possess high cytotoxic and anti-proliferative effects in HeLa cells. The cytotoxic effect occurred via apoptosis, being accompanied by a return of pHe/pHi towards normal values as for other CA IX inhibitors investigated earlier.

Inhibitory activity against carbonic anhydrase IX and XII as a candidate selection criterion in the development of new anticancer agents

“…Disappointingly, a large fraction of publications on the subject reported compounds' cytotoxicity data obtained in normoxic conditions thus making the involvement of hCA IX and XII debateable [30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45] . Although such testing can be relevant in some cases, we consider these conditions irrelevant as long as antiproliferative activity of hCA inhibitors is concerned.…”

“…Understanding the significance of the candidate molecule prioritisation problem in question is essential while ignoring it may lead to many promising compounds being overlooked in want of more potent hCA IX/XII inhibitors. Aiming to draw a more informative picture, we have graphically represented the relationship between the anticancer effect (in this case, irrespective of the specific experimental conditions employed in various studies) and the hCA IX/XII inhibitory activity of the compounds [30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][49][50][51][52][53][54][55][56][57][58][71][72][73][74] . In order to summarise the somewhat heterogeneous literature data, we have visualised the reported antiproliferative agents in the plots with the Y-axis displaying K i 's against hCA IX (Figures S1 and S2) and hCA XII ( Figures S3 and S4).…”

Cornus Mas L improves Antioxidant Status in the Liver, Lung, Kidney, Testis and Brain of Ehrlich Ascites Tumor Bearing Mice

“…The C. mas L. fruit extract is an anticancer drug that is widely used in the treatment of cancers. Nonetheless, cancer cells interacting with oxygen and ions lead to an increase in superoxide and another ROS (Jia-Fu et al, 2012;Koyuncu et al, 2019;Reinert et al, 2013). An increase in the tumor-related ROS production in the tissues causes various side effects due to its cytotoxic and genotoxic effects.…”

Carbonic Anhydrase Inhibitor Acetazolamide Enhances CHOP Treatment Response and Stimulates Effector T-Cell Infiltration in A20/BalbC Murine B-Cell Lymphoma

“…The potential of CAs, and more specifically cancer related CAIX and CAXII as biological targets for anti-tumor therapy, has been intensively studied in the past two decades [7,17,19,21]. As the central paradigm, the inhibition of their pH neutralization effect effectively contributes to tumor cell damage by maintaining intracellular acidosis.…”

“…For this reason, there is profound knowledge regarding the dosage, pharmacokinetics, and toxicity for the prominent groups of inhibitory compounds. Currently used CA inhibitors are of non-selective effect with a considerable affinity to block tumor related isoenzyme CAIX and CAXII activity which could be specifically demonstrated in hypoxic cancer cells in vitro [17][18][19]. Moreover, the development of isoenzyme specific inhibitors for cancer therapy resulted in promising data.…”