Anticancer activity of Stemona tuberosa (wild asparagus) against type-II human lung adenocarcinoma (A549) cells and identification of SRC inhibitor using integrated network pharmacology and molecular dynamic simulation.

Abstract

Stemona tuberosa is widely recognized for its traditional applications as an anti-cancer agent. This study aimed to assess the anti-cancer properties of S. tuberosa in human lung adenocarcinoma A549 cells. Among the various solvent extracts of S. tuberosa, the methanolic extract showed the highest toxicity against A549 cells. The S. tuberosa extract elicited cytotoxic effects and suppressed colony formation in A549 cells in a dose-dependent manner. S. tuberosa activity was further supported by AO/EtBr staining, increased caspase 3/6 activity, upregulation of pro-apoptotic genes, DNA damage, and elevated lipid peroxidation, with decreasing antioxidant levels. LC-MS analysis identified 80 predominant secondary metabolites in the methanolic extracts of S. tuberosa. A network pharmacology study identified SRC as the primary target of compounds identified from S. tuberosa. SRC protein is crucial for advancing lung cancer because of its function in cell proliferation, survival, and metastasis. Among the various compounds identified from S. tuberosa extract, 4-Azatricyclo [4.3.1.13,8] undecan-5-one (ADE) (- 10.88 kcal/mol) and Dihydro-normorphine, 3-desoxy- (DNY) (- 10.83 kcal/mol) exhibited notable binding affinities for SRC. Further analysis using molecular dynamics simulations (100 ns) validated the stability of SRC-ligand complexes, with RMSD of 1.8 and 2.2 Å for ADE and DNY, respectively, alongside the establishment of essential hydrogen bonds with pivotal residues, including ASP408, ALA403, and THR438. Finally, gmx._MMPBSA showed favourable ΔGbind values for ADE (- 15.06 ± 0.11 kcal/mol) and DNY (- 15.66 ± 0.25 kcal/mol), which highlights the significant potential of ADE and DNY as effective SRC inhibitors, suggesting S. tuberosa as a novel candidate for cancer therapy.