TY - JOUR

T1 - Combination of Carbonic Anhydrase Isoform IX Inhibitors and Gefitinib Suppresses on the Invasive Potential of Non-Small Cell Lung Cancer Cells

AU - Тюряева, Ирина Ивановна

AU - Шаронова, Татьяна Валерьевна

AU - Шетнев, Антон

AU - Кожухов, Павел

AU - Семчук, Ольга

AU - Бунев, Александр

AU - Хотин, Михаил

AU - Агеев, Сергей Вадимович

AU - Холмуродова, Дилафруз

AU - Ризаев, Джасур

AU - Семёнов, Константин Николаевич

AU - Шаройко, Владимир Владимирович

PY - 2024/12

Y1 - 2024/12

N2 - Abstract: 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.

AB - Abstract: 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.

KW - 1,2,4-oxadiazoles

KW - cancer

KW - combination therapy

KW - gefitinib

KW - human carbonic anhydrase inhibitors

KW - human lung adenocarcinoma A549 cells

KW - hypoxia

KW - sulfonamides

KW - tumor microenvironment

UR - https://www.mendeley.com/catalogue/d56fda51-0708-3b1f-92c1-c348c5ea19df/

U2 - 10.1134/s0006297924120113

DO - 10.1134/s0006297924120113

M3 - Article

VL - 89

SP - 2227

EP - 2237

JO - Biochemistry (Moscow)

JF - Biochemistry (Moscow)

SN - 0006-2979

IS - 12-13

ER -