Swertiamarin Sensitizes KYSE-150 Esophageal Squamous Cell CarcinomaCells to Cisplatin Cytotoxicity by Potentially Interacting with DrugResistance Pathways

Background: Esophageal Squamous Cell Carcinoma (ESCC) is the most aggressive esophageal cancer subtype, with poor therapeutic outcomes due to chemoresistance to first-line chemotherapeutic agents, including cisplatin and 5-fluorouracil (5-FU). Swertiamarin (STM), a natural iridoid glycoside, possesses various pharmacological properties, including anticancer activity, but its chemosensitizing role in ESCC remains elusive. This study aimed to investigate the chemosensitizing potential of STM on cisplatin and 5-FU in ESCC KYSE-150 cells, supported by in silico molecular docking analyses. Methods: In silico drug-likeness and toxicological profile of STM were predicted. Cytotoxicity of STM, cisplatin, and 5-FU in ESCC cells (KYSE-150), normal esophageal epithelial cells (HET-1A), and Vero cells was assessed by MTT assay. STM’s chemosensitizing potential was investigated using a pre-treatment model with its 20% Inhibitory Concentration (IC20) and halfmaximal Inhibitory Concentration (IC50) for 2, 4, and 6 hours. Molecular docking was performed to examine STM’s binding affinity and interactions with target proteins. Results and Discussion: STM revealed favorable predicted drug-likeness properties and toxicological profile, alongside selective cytotoxicity against KYSE-150 cells. Although STM pretreatment slightly increased cisplatin’s IC50, the increased cytotoxic effects over time suggest its potential chemosensitizing activity. No notable interaction was observed with 5-FU. Docking analysis revealed strong binding affinity of STM to chemoresistance-associated proteins MAPK1 (–8.774 kcal/mol), mTOR (–8.764 kcal/mol), ABCC2 (–7.949 kcal/mol), and NF-κB (- 7.914 kcal/mol), supporting potential underlying molecular mechanisms. Conclusion: Cisplatin’s improved cytotoxic pattern over time with STM pre-treatment, alongside favorable preliminary in silico analyses, warrant further investigation into STM’s potential role as a chemosensitizer in ESCC chemotherapy.