Characterization of Acquired Capecitabine Resistance in Mkn-45 Gastric Cancer Cells Reveals Preserved Apoptotic Sensitivity Publisher Pubmed



Mohseni H S ; Tavajohi S ; Kebriaeezadeh A ; Ghahremani M H ; Ostad S N
Source: DARU, Journal of Pharmaceutical Sciences Published:2026

Abstract

Background: Capecitabine (Cap) is widely used in the treatment of advanced gastric cancer; however, the emergence of acquired resistance remains a major obstacle to its long-term efficacy. Although several gastric cancer models resistant to 5-fluorouracil (5-FU) have been reported, experimentally characterized gastric cancer models of Cap resistance remain limited. Objectives: This study aimed to establish and characterize a Cap-resistant MKN-45 gastric cancer cell model. with a focus on phenotypic alterations associated with acquired drug adaptation. Methods: A Cap-resistant MKN-45 subline (MKN-45/R-CapIC₆₀) was generated through exposure of parental MKN-45 cells to gradually increasing concentrations of Cap. Cell viability was evaluated using the MTT assay. Morphological alterations were examined by phase-contrast microscopy, while apoptosis, cell-cycle distribution, and surface c-Met expression were analyzed by flow cytometry. Results: The established resistant subline exhibited a moderate level of Cap resistance, with an approximately 2- to 4-fold increase in the resistance index (RI) compared with the parental cells. Resistant cells showed morphological remodeling characterized by an elongated spindle-like morphology and increased adherence to the culture surface compared with parental cells. Surface c-Met expression was altered in resistant cells and further decreased following Cap exposure. Despite the acquisition of a resistance phenotype, Cap exposure retained biological activity in resistant cells by reducing proliferation, altering cell-cycle distribution through impaired G1/S transition, and increasing late apoptotic/necrotic populations. Conclusions: The findings suggest that the established Cap-resistant gastric cancer cell model retains responsiveness to Cap exposure despite the acquisition of a resistance phenotype. This model may provide a useful platform for investigating early phenotypic adaptations associated with the development of drug resistance in gastric cancer. © The Author(s), under exclusive licence to Tehran University of Medical Sciences 2026.