Effective Anticancer Potential of a New Sulfonamide as a Carbonic Anhydrase IX Inhibitor Against Aggressive Tumors

• Published in: ChemMedChem 2024-05, Vol.19 (9), p.e202300680-e202300680
• Main Authors: Koyuncu, Ismail, Temiz, Ebru, Güler, Eray Metin, Durgun, Mustafa, Yuksekdag, Ozgür, Giovannuzzi, Simone, Supuran, Claudiu T
• Format: Article
• Language: English
• Subjects: Acidity; Anticancer properties; Apoptosis; BIM protein; Breast cancer; Carbonic anhydrase; Caspase; Cell proliferation; Cytology; Cytotoxicity; DIABLO protein; FasL protein; G1 phase; Heat shock proteins; Hsp27 protein; Hsp60 protein; Hsp70 protein; Hypoxia; Inhibitors; Isoforms; Membranes; p53 Protein; Proteins; Regulatory proteins; Solid tumors; Sulfonamides; Survivin; Tumor necrosis factor; Tumors; Wound healing; XIAP protein
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.202300680

This study examines efficiency of a newly synthesized sulfonamide derivative 2-bromo-N-(4-sulfamoylphenyl)propanamide (MMH-1) on the inhibition of Carbonic Anhydrase IX (CA IX), which is overexpressed in many solid tumors including breast cancer. The inhibitory potential of MMH-1 compound against its four major isoforms, including cytosolic isoforms hCA I and II, as well as tumor-associated membrane-bound isoforms hCA IX and XII, was evaluated. To this context, the cytotoxic effect of MMH-1 on cancer and normal cells was tested and found to selectively affect MDA-MB-231 cells. MMH-1 reduced cell proliferation by holding cells in the G0/G1 phase (72 %) and slowed the cells' wound healing capacity. MMH-1 inhibited CA IX under both hypoxic and normoxic conditions and altered the morphology of triple negative breast cancer cells. In MDA-MB-231 cells, inhibition of CA IX was accompanied by a decrease in extracellular pH acidity (7.2), disruption of mitochondrial membrane integrity (80 %), an increase in reactive oxygen levels (25 %), and the triggering of apoptosis (40 %). In addition, the caspase cascade (CASP-3, -8, -9) was activated in MDA-MB-231 cells, triggering both the extrinsic and intrinsic apoptotic pathways. The expression of pro-apoptotic regulatory proteins (Bad, Bax, Bid, Bim, Cyt-c, Fas, FasL, TNF-a, TNF-R1, HTRA, SMAC, Casp-3, -8, P21, P27, and P53) was increased, while the expression of anti-apoptotic proteins, apoptosis inhibitor proteins (IAPs), and heat shock proteins (HSPs) (Bcl-2, Bcl-w, cIAP-2, HSP27, HSP60, HSP70, Survivin, Livin, and XIAP) was decreased. These results propose that the MMH-1 compound could triggers apoptosis in MDA-MB-231 cells via the pH/MMP/ROS pathway through the inhibition of CA IX. This compound is thought to have high potential and promising anticancer properties in the treatment of aggressive tumors.