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Inhibition of Carbonic Anhydrase Using SLC-149: Support for a Noncatalytic Function of CAIX in Breast Cancer
Mam Y Mboge1, Jacob Combs1, Srishti Singh1
1Department of Biochemistry and Molecular Biology, University of Florida, 1200 Newell Drive, Gainesville, Florida 32610, United States.
Abstract:
Carbonic anhydrase IX (CAIX) is considered a target for therapeutic intervention in solid tumors. In this study, the efficacy of the inhibitor, 4-(3-(2,4-difluorophenyl)-oxoimidazolidin-1-yl)benzenesulfonamide (SLC-149), is evaluated on CAIX and a CAIX-mimic. We show that SLC-149 is a better inhibitor than acetazolamide against CAIX. Binding of SLC-149 thermally stabilizes CAIX-mimic at lower concentrations compared to that of CAII. Structural examinations of SLC-149 bound to CAIX-mimic and CAII explain binding preferences. In cell culture, SLC-149 is a more effective inhibitor of CAIX activity in a triple-negative breast cancer cell line than previously studied sulfonamide inhibitors. SLC-149 is also a better inhibitor of activity in cells expressing CAIX versus CAXII. However, SLC-149 has little effect on cytotoxicity, and high concentrations are required to inhibit cell growth, migration, and invasion. These data support the hypothesis that CAIX activity, shown to be important in regulating extracellular pH, does not underlie its ability to control cell growth.
Insights
The novel inhibitor SLC-149 effectively targets carbonic anhydrase IX (CAIX) in cancer cells, outperforming existing drugs. However, it minimally impacts cancer cell growth, suggesting CAIX’s role in proliferation is independent of its pH regulation function.
Area of Science:
- Biochemistry
- Oncology
- Pharmacology
Background:
- Carbonic anhydrase IX (CAIX) is a key therapeutic target in solid tumors.
- Understanding CAIX inhibitors is crucial for cancer treatment development.
Purpose of the Study:
- To evaluate the efficacy of a novel inhibitor, SLC-149, against CAIX and a CAIX-mimic.
- To compare SLC-149's inhibitory activity with existing drugs like acetazolamide.
- To investigate the mechanism of SLC-149 binding and its effects on cancer cell behavior.
Main Methods:
- Enzyme inhibition assays using CAIX and CAIX-mimic.
- Thermal stabilization studies.
- Structural analysis of inhibitor-enzyme complexes.
- Cell culture experiments with triple-negative breast cancer cell lines.
- Assessment of cytotoxicity, cell growth, migration, and invasion.
Main Results:
- SLC-149 is a more potent inhibitor of CAIX than acetazolamide.
- SLC-149 demonstrates preferential binding to CAIX over CAII and CAXII.
- Structural studies elucidate the binding preferences of SLC-149.
- SLC-149 effectively inhibits CAIX activity in triple-negative breast cancer cells.
- High concentrations of SLC-149 are required to inhibit cell growth, migration, and invasion.
Conclusions:
- SLC-149 is a promising CAIX inhibitor with potential therapeutic applications.
- CAIX's role in regulating extracellular pH is distinct from its function in controlling cancer cell proliferation.
- Further research is needed to develop effective CAIX-targeted therapies that impact cancer progression.
