Comparative anti-cancer properties of carene isoforms induced apoptotic cell death in stomach and lung cancer cell...

Carene isoforms, particularly 3-carene, are naturally occurring bicyclic monoterpenes from Piper nigrum that exhibit promising anti-cancer properties due to their ability to induce apoptosis in malignant cells, but its mechanisms in gastric (AGS) and lung (H727) cancer cells remain unexplored. In this study, we investigated the effects of 3-carene on cell viability, anti-proliferative activity, and apoptosis in AGS and H727 cells treated with varying concentrations using MTT assays, light and fluorescence microscopy, flow cytometry, qRT-PCR, and molecular docking analyses. Pharmacokinetics and dynamics were assessed via ADMET analysis and simulations. Results demonstrated that 3-carene significantly reduced cell viability in both cell lines, with IC₅₀ values of 12.30 µg/mL for AGS cells and 12.61 µg/mL for H727 cells, surpassing the efficacy of cisplatin. Flow cytometry confirmed dose-dependent induction (Annexin V/PI) of apoptosis and significant G_O/G₁ phase cell cycle arrest. Consistent with these findings, molecular docking and dynamic simulations analyses revealed strong binding affinity and stable interactions of 3-carene with key cell cycle regulatory proteins, suggesting a direct molecular basis for the observed cell cycle arrest. Furthermore, molecular study revealed upregulation of pro-apoptotic genes including Bax and Caspase-3, while the anti-apoptotic gene Bcl-2 was downregulated. Taken together, these data indicate that 3-carene exerts anti-cancer effects by promoting apoptosis through the intrinsic mitochondrial route and disrupting cell cycle progression, making it a promising therapeutic agent for metastatic gastric and lung malignancies.