Comparative effects of arsenic trioxide and chemotherapy on Chk1 and CDC25 gene expression in gastric cancer cells AGS and MKN45: a potential therapeutic strategy.

Abstract

Background: Gastric cancer (GC) remains a significant global health burden, particularly in East Asia, where it is a leading cause of cancer-related morbidity and mortality. Despite advancements in chemotherapy, the development of chemoresistance continues to undermine the efficacy of standard treatments such as Docetaxel and Oxaliplatin. Arsenic trioxide (ATO) has emerged as a potential therapeutic agent capable of overcoming resistance by targeting DNA repair mechanisms, particularly through the downregulation of Checkpoint Kinase 1 (Chk1). This study investigates the cytotoxic effects of ATO and its capacity to enhance chemotherapy efficacy in GC cells.

Methods: AGS and MKN-45 gastric cancer cell lines were exposed to ATO, Docetaxel, Oxaliplatin, and their combinations. Cell viability was assessed via the MTT assay, while Chk1 and CDC25 expressions at the mRNA and protein levels was analyzed using real-time PCR and Western blotting. Statistical analyses were performed using ANOVA and Tukey's post hoc test.

Results: The MTT assay revealed significant dose- and time-dependent reductions in cell viability, with combination treatments achieving the most pronounced effects. The greatest cytotoxicity was observed with 4 µM ATO combined with 2500 µM Docetaxel or 100 µM Oxaliplatin, showing a high level of statistical significance (p < 0.0001). Additionally, ATO monotherapy significantly downregulated Chk1 and CDC25 expressions (p < 0.05), while its combination with chemotherapeutic agents further enhanced Chk1 and CDC25 suppressions, with ATO-Docetaxel demonstrating the most pronounced effect (p < 0.01).

Conclusions: These findings highlight ATO's potential to sensitize GC cells to chemotherapy by impairing DNA repair mechanisms and inducing synergistic cytotoxicity. ATO holds promise as an adjuvant therapeutic agent for overcoming chemoresistance in gastric cancer.