فهرست نشریات علمی دسترسی آزاد ایران

Lung Cancer (LC), a prominent cause of cancer-related mortality globally, necessitates innovative therapies with strong pharmacokinetics. This study evaluated the anticancer potential of sakuranin in A549 LC cells and a xenograft model, focusing on cytotoxicity, pro-oxidative, apoptotic, anti-metastatic, and cell cycle arrest effects, alongside molecular interactions with PI3K/AKT/mTOR pathway proteins. The physicochemical properties and Absorption, Distribution, Metabolism, Excretion (ADME)/toxicity profile were analyzed via SwissADME and ProTox-3.0. Cytotoxicity was assessed via MTT assay, Reactive-Oxygen-Species (ROS) using DiChloro-dihydro-Fluorescein-DiAcetate (DCFH-DA) fluorescence, Mitochondrial Membrane Potential (MMP) via Rhodamine (Rh)-123 staining, apoptosis via 4',6-diamidino-2-phenylindole (DAPI)-based nuclear morphology, and cell cycle arrest via flow cytometry. Anti-migratory/invasive effects were tested using transwell assays. In vivo efficacy was observed in a xenograft model, and molecular docking evaluated binding interactions to PI3K/AKT/mTOR proteins. Sakuranin complied with Lipinski’s rules, demonstrating favorable solubility and bioavailability. It exhibited dose-dependent cytotoxicity in A549 cells (IC₅₀: 74.22 µg/mL; 82% viability reduction at the highest dose). ROS levels tripled, while MMP depolarization reduced fluorescence intensity by 59%. Apoptotic nuclear changes were observed, and cell cycle analysis revealed 70% G2/M phase arrest. Migration and invasion decreased by 70% and 65%, respectively. In vivo, a 200 mg/kg dose resulted in a 90% drop in tumor volume and a 72% drop in tumor weight. Molecular docking studies confirmed strong interactions of sakuranin with PI3K (-9.2 kcal/mol), AKT (-10.5 kcal/mol), mTOR (-8.7 kcal/mol), and ERK (-8.1 kcal/mol), suggesting its role in modulating the PI3K/AKT/mTOR signaling cascade. Conclusion: Sakuranin demonstrates potent cytotoxic, pro-apoptotic, and anti-metastatic effects in LC models. Its interaction with key signaling proteins underscores its therapeutic potential. These findings advocate further exploration of sakuranin as a promising LC treatment candidate targeting the PI3K/AKT/mTOR axis.