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

Abstract

AbstractThis 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.