Tiliacorinine, a bisbenzylisoquinoline alkaloid from Tiliacora triandra, induces cell apoptosis of lung adenocarcinoma by inhibiting STAT3 and Akt expressions

Objective Non-small lung cancer (NSCLC) is the leading cause of death worldwide, in which lung adenocarcinoma (LUAD) is the most prevalent subtype. Epidermal growth factor receptor (EGFR) mutations are frequently found in LUAD and often lead to therapeutic resistance. This study aimed to investigate the effects of tiliacorinine (TC), a natural bisbenzylisoquinoline alkaloid from Tiliacora triandra , on LUAD cells with various EGFR statuses, including those harboring the EGFR-tyrosine kinase inhibitor (TKI) resistance. Methods TC was isolated from T. triandra using organic solvents and purified by chromatographic methods, while its structure was elucidated by 1 H and 13 C nuclear magnetic resonance spectroscopy. Cytotoxic effects of TC were investigated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell apoptosis was determined using annexin V-FITC staining and flow cytometry. Molecular mechanisms underlying TC-induced cell apoptosis were investigated using Western blotting and in silico molecular docking. Results TC significantly induced apoptosis in LUAD cells, regardless of EGFR mutation status. Moreover, cells harboring the EGFR T790M mutation, which exhibit EGFR-TKI resistance, also showed high sensitivity to TC. TC significantly downregulated anti-apoptotic genes, thereby activating the intrinsic apoptotic pathways. These results were consistent with downregulation of STAT3 and Akt expression, upstream activators of anti-apoptotic genes. Finally, molecular docking demonstrated TC's potential binding to the EGFR T790M mutation, with a binding energy comparable to that of osimertinib, a targeted therapy for EGFR-TKI-resistant mutations. Conclusion TC exerted pro-apoptotic effects on NSCLC cells, demonstrating promise as a therapeutic agent for NSCLC and other cancers with EGFR-TKI-resistant mutations.