β-Thujaplicin modulates the ODC-ROS-linked apoptosis in H460 lung cancer cells.

This study explored the antiproliferative effects of β-thujaplicin, a natural tropolone derivative, in the non-small-cell lung cancer (NSCLC) cell lines H460 and A549 and in L132 normal lung epithelial cells, using MTT, NRU, and SRB assays. β-Thujaplicin exhibited concentration-dependent cytotoxicity in H460 and A549 cells but had minimal effect on L132 cells. Mechanistic studies in H460 cells showed suppression of ornithine decarboxylase (ODC) activity and ODC mRNA expression, along with alterations in polyamine metabolite abundance detected by LC-HRMS. Fluorescence microscopy, flow cytometry, and gene expression analysis revealed increased reactive oxygen species (ROS) generation, apoptosis, and cell cycle arrest, suggesting the involvement of the ODC-polyamines axis in these responses. β-Thujaplicin also reduced migration and invasion, accompanied by changes in apoptosis- and epithelial-mesenchymal transition-associated markers. Molecular docking and in silico ADMET analysis suggested an interaction of β-thujaplicin with ODC and predicted favorable drug-like and pharmacokinetic properties that require experimental validation. In the Ehrlich ascites carcinoma (EAC) model, β-thujaplicin reduced tumor burden and increased oxidative stress, providing preliminary evidence of its antitumor activity. However, as this EAC model does not recapitulate NSCLC-specific biology, these findings should be considered proof-of-concept rather than validation of the H460-derived mechanism. Overall, β-thujaplicin shows promising anticancer potential and needs further assessment in NSCLC-specific xenograft and orthotopic in vivo models.