Combination of Carbonic Anhydrase Isoform IX Inhibitors and Gefitinib Suppresses on the Invasive Potential of Non-Small Cell Lung Cancer Cells

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Alexander S. Bunev¹, Anton A. Shetnev², Olga S. Shemchuk³, Pavel K. Kozhukhov³, Tatyana V. Sharonova⁴, Irina I. Tyuryaeva^4,5, Mikhail G. Khotin⁵, Sergey V. Ageev^3,4, Dilafruz K. Kholmurodova⁶, Jasur A. Rizaev⁶, Konstantin N. Semenov^3,4,6, Vladimir V. Sharoyko^1,3,4,6,a*

¹Medicinal Chemistry Center, Togliatti State University, 445020 Togliatti, Russia

²Institute of Biophysics of the Future, 141701 Dolgoprudny, Moscow Region, Russia

³Pavlov First St. Petersburg State Medical University, 197022 St. Petersburg, Russia

⁴St. Petersburg State University, 199034 St. Petersburg, Russia

⁵Institute of Cytology, Russian Academy of Sciences, 194064 St. Petersburg, Russia

⁶Scientific and Practice Center for Immunology, Allergology and Human Genomics, Samarkand State Medical University, Samarkand, 100400, Uzbekistan

^* To whom correspondence should be addressed.

Received: June 10, 2024; Revised: October 24, 2024; Accepted: November 5, 2024

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Human carbonic anhydrase IX (CAIX) plays a key role in maintaining pH homeostasis of malignant neoplasms, thus creating a favorable microenvironment for the growth, invasion, and metastasis of tumor cells. Recent studies have established that inhibition of CAIX expressed on the surface of tumor cells significantly increases the efficacy of classical chemotherapeutic agents and makes it possible to suppress the resistance of tumor cells to chemotherapy, as well as to increase their sensitivity to drugs (in particular, to reduce the required dose of cytostatic agents). In this work, we studied the ability of new CAIX inhibitors based on substituted 1,2,4-oxadiazole-containing primary aromatic sulfonamides, to potentiate the cytostatic effect of gefitinib (selective inhibitor of epidermal growth factor receptor tyrosine kinase domain) under hypoxic conditions. We investigated a combined effect of gefitinib and CAIX inhibitors 4-(3-phenyl-1,2,4-oxadiazol-5-yl)thiophene-2-sulfonamide (1), 4-(5-(thiophene-3-yl)-1,2,4-oxadiazol-3-yl)benzenesulfonamide (2), 4-(3-(pyridin-2-yl)-1,2,4-oxadiazol-5-yl)thiophene-2-sulfonamide (3), and 4-(5-methyl-1,2,4-oxadiazol-3-yl)benzenesulfonamide (4) on gefitinib cytotoxicity, cell proliferation, activation of caspases-3/7, and cell cycle control in human lung adenocarcinoma A549 cells. It was found that the combinations of compounds 1 and 2 with gefitinib suppressed the invasive potential of A549 cells. Compound 1 had the greatest effect and can be considered as a promising candidate for further research.

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KEY WORDS: combination therapy, tumor microenvironment, human carbonic anhydrase inhibitors, human lung adenocarcinoma A549 cells, cancer, hypoxia, sulfonamides, 1,2,4-oxadiazoles, gefitinib

DOI: 10.1134/S0006297924120113

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