Sakuranin Targets Lung Cancer: In Vitro, in Vivo, and in Silico Analysis

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 A۵۴۹ LC cells and a xenograft model, focusing on cytotoxicity, pro-oxidative, apoptotic, anti-metastatic, and cell cycle arrest effects, alongside molecular interactions with PI۳K/AKT/mTOR pathway proteins. The physicochemical properties and Absorption, Distribution, Metabolism, Excretion (ADME)/toxicity profile were analyzed via SwissADME and ProTox-۳.۰. 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)-۱۲۳ staining, apoptosis via ۴',۶-diamidino-۲-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 PI۳K/AKT/mTOR proteins. Sakuranin complied with Lipinski’s rules, demonstrating favorable solubility and bioavailability. It exhibited dose-dependent cytotoxicity in A۵۴۹ cells (IC₅₀: ۷۴.۲۲ µg/mL; ۸۲% viability reduction at the highest dose). ROS levels tripled, while MMP depolarization reduced fluorescence intensity by ۵۹%. Apoptotic nuclear changes were observed, and cell cycle analysis revealed ۷۰% G۲/M phase arrest. Migration and invasion decreased by ۷۰% and ۶۵%, respectively. In vivo, a ۲۰۰ mg/kg dose resulted in a ۹۰% drop in tumor volume and a ۷۲% drop in tumor weight. Molecular docking studies confirmed strong interactions of sakuranin with PI۳K (-۹.۲ kcal/mol), AKT (-۱۰.۵ kcal/mol), mTOR (-۸.۷ kcal/mol), and ERK (-۸.۱ kcal/mol), suggesting its role in modulating the PI۳K/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 PI۳K/AKT/mTOR axis.

کلیدواژه ها:

Natural products ، Apoptosis ، Cell-cycle ، Reactive Oxygen Species ، Migration ، invasion ، Mitochondrial membrane potential