Oxaliplatin is widely used to treat advanced gastric cancer (GC), but drug resistance limits its long-term effectiveness. Notch signaling has been implicated in promoting chemoresistance in several cancers, including GC. We investigated whether the Notch pathway contributes to oxaliplatin resistance in GC and whether its inhibition by IMR-1 could restore drug sensitivity. Oxaliplatin-resistant GC cell lines (SGC-7901R and MGC-803R) were established and treated with IMR-1, oxaliplatin, or their combination. Cell viability, colony formation, apoptosis, and protein expression were assessed following treatment with IMR-1, oxaliplatin, or both. An in vivo xenograft model was used to validate the therapeutic effect. Resistant GC cells exhibited elevated Notch1 and Notch2 expression and reduced sensitivity to oxaliplatin. IMR-1 treatment significantly suppressed Notch signaling and increased oxaliplatin-induced apoptosis in these cells. Combination treatment reduced cell viability and colony numbers, increased Bax expression, and reduced Bcl-2 levels. In vivo, the combination therapy reduced tumor volume compared to control and significantly lowered Ki-67, Notch1, and Notch2 expression in tumor tissues. IMR-1 effectively reverses oxaliplatin resistance in GC cells by blocking Notch signaling and promoting apoptosis, supporting IMR-1 as a promising agent to improve oxaliplatin-based therapy in patients with resistant GC.
Xu et al. (Mon,) studied this question.