Anticancer effects of emetine against cisplatin resistant pancreatic cancer cells via activation of Cyto-c/Caspase-9/Caspase-3/Bax/Bad axis

This investigation examines the potential pharmacotherapeutic efficacy of emetine, a natural alkaloid, against pancreatic ductal carcinoma, utilizing the PaCa3 cell line as a model. Employing a multifaceted approach, the study explores emetine's impact on cell viability, clonogenic potential, and apoptotic pathways, unravelling its molecular mechanisms. Additionally, an in-vivo assessment is conducted to evaluate emetine's antitumor efficacy against PaCa3 xenografts. Under standard conditions, PaCa3 cells were treated with varying emetine concentrations and subjected to MTT, clonogenic, DAPI, AO/EB, Annexin V-FITC/PI, and Western blot assays. In-vivo experiments involved the administration of emetine to female nude mice with PaCa3 xenografts, with subsequent measurement of tumor weight and volume. Statistical analyses included Tukey-test and ANOVA. Emetine demonstrated a significant and dose- and time-dependent cytotoxic effect on PaCa3 cells, reducing viability from 98% to 8% (***p<0.001). Clonogenic assay indicated a substantial inhibition of colony formation. DAPI staining revealed nuclear chromatin condensation, while AO/EB staining indicated heightened apoptosis. Annexin V-FITC/PI assay exhibited a dose-dependent decrease in normal cell viability and an increase in apoptotic events. Western blot analysis showcased concentration-dependent downregulation of anti-apoptotic Bcl-2 and upregulation of pro-apoptotic markers. In-vivo experiments illustrated a dose-dependent reduction in tumor weight (5 g to 1.6 g) and volume (2400 mm³ to 844 mm³) with emetine treatment. In conclusion, emetine emerges as a potent anticancer agent against pancreatic ductal carcinoma, exhibiting cytotoxicity, clonogenic inhibition, and apoptotic induction in PaCa3 cells. The in-vivo study further highlights its promising therapeutic potential, laying the groundwork for future clinical studies in pancreatic cancer treatment.