Babaei Shadi, Nikbakht Mohsen, Majd Ahmad, Mousavi Seyed Asadoullah
Department of Biology, North Tehran Branch, Islamic Azad University, Tehran, Iran.
Research Institute for Oncology, Hematology and Cell Therapy, Tehran University of Medical Sciences, Tehran, Iran.
Mol Biol Rep. 2025 Feb 4;52(1):198. doi: 10.1007/s11033-025-10313-9.
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.
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.
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).
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.
胃癌（GC）仍然是一个重大的全球健康负担，尤其是在东亚地区，它是癌症相关发病和死亡的主要原因。尽管化疗取得了进展，但化疗耐药性的出现继续削弱多西他赛和奥沙利铂等标准治疗的疗效。三氧化二砷（ATO）已成为一种潜在的治疗剂，能够通过靶向DNA修复机制克服耐药性，特别是通过下调检查点激酶1（Chk1）。本研究调查了ATO的细胞毒性作用及其增强GC细胞化疗疗效的能力。
将AGS和MKN-45胃癌细胞系暴露于ATO、多西他赛、奥沙利铂及其组合中。通过MTT法评估细胞活力，同时使用实时PCR和蛋白质印迹法分析Chk1和CDC25在mRNA和蛋白质水平的表达。使用方差分析和Tukey事后检验进行统计分析。
MTT分析显示细胞活力有显著的剂量和时间依赖性降低，联合治疗效果最为显著。在4 µM ATO与2500 µM多西他赛或100 µM奥沙利铂联合使用时观察到最大的细胞毒性，具有高度统计学意义（p < 0.0001）。此外，ATO单药治疗显著下调Chk1和CDC25的表达（p < 0.05），而其与化疗药物联合使用进一步增强了Chk1和CDC25的抑制作用，ATO-多西他赛联合显示出最显著的效果（p < 0.01）。
这些发现突出了ATO通过损害DNA修复机制和诱导协同细胞毒性使GC细胞对化疗敏感的潜力。ATO有望作为克服胃癌化疗耐药性的辅助治疗剂。
