Dual-Targeting of β-Tubulin and Carbonic Anhydrase IX by Albendazole-Etoricoxib Combination Induces Synergistic Cytotoxicity and Energetic Strangulation in Cervical Cancer Cells

Objective: This study was performed to evaluate the cytotoxic effects and synergistic interactions of Albendazole combined with Etoricoxib on HeLa cervical carcinoma cells, emphasizing mechanisms involving disruption of glycolytic metabolism and cellular pH regulation. Materials and Methods: The study investigated the cytotoxic effects of Albendazole, Etoricoxib, their combination, and 5-Fluorouracil (5-FU) on HeLa cells and normal human foreskin fibroblasts (HFF) via MTT assays. It also calculated the Combination Index (CI) and Dose Reduction Index (DRI) using CompuSyn software to evaluate drug synergy. Furthermore, lactate production and carbonic anhydrase activity were measured to analyze glycolytic flux and pH regulation, and were complemented by molecular docking of the drugs with β-tubulin and carbonic anhydrase IX. Results: The combination of Albendazole and Etoricoxib exhibited significant synergistic cytotoxic effects against HeLa cells, compared to either agent alone or 5-Fluorouracil (5-FU). The combination also showed high selectivity, indicating a sparing impact on HFF cells, unlike 5-FU. Furthermore, the combined treatment markedly inhibited lactate production by 85.1% and carbonic anhydrase activity by 86.3%. Molecular docking studies corroborated these findings by revealing stable binding interactions of Albendazole with β-tubulin and Etoricoxib with CA-IX, with docking scores of -6.7 and -7.1 kcal/mol, respectively, supporting a dual-targeting mechanism. Conclusion: The combined use of Albendazole and Etoricoxib produces a synergistic effect on cervical cancer cells by disrupting glycolytic metabolism and cellular pH regulation. This targeted approach offers a promising way to overcome chemoresistance and lessen toxicity, thereby improving therapeutic effectiveness in cervical cancer treatment.