Natural compounds naringin and nobiletin synergistically inhibit the PI3K/AKT/mTOR pathway in NSCLC: molecular docking and cytotoxicity studies.

Non-small-cell lung cancer (NSCLC) is the most common malignant type, and the present treatments do not offer the most effective outcomes for therapy. The capacity of tumor cells to proliferate and migrate is closely associated with the aberrant expression of the PI3K/AKT signalling cascade. Thus, bioactive substances that may prevent PI3K/AKT signalling activation could ultimately be employed as NSCLC treatment agents. The current investigation considered the efficacy of hindering the growth of lung cancer cells (A549) by blocking the PI3K/AKT intervening signalling pathways using the natural drugs naringin (NAR) and nobiletin (NOB). This was further supported by molecular docking analysis. The cells were assessed for a number of investigations after they had been subjected to different concentrations (0-40 µM) of NAR and NOB (NAR + NOB) for 24 h. The MTT assay was used to examine NAR + NOB-induced cytotoxicity. DCFH-DA stain was used to measure ROS. Multimodal (AO/EtBr) staining was used to investigate apoptotic changes, and the appropriate fluorescence staining tests were used to evaluate MMP levels in A549 cells. The progression of cells and apoptosis was measured by flow cytometry. The core target's binding impact was confirmed by molecular docking, confirming whether the PI3K, AKT, mTOR, pTEN, and PDK-1 protein targets interact with NAR and NOB. According to the findings, NAR and NOB have a high binding energy with the PI3K, AKT, mTOR, pTEN, and PDK-1 targets, especially PI3K. The combination of NAR + NOB causes significant cytotoxicity in A549 cells. Additionally, A549 cells treated with NAR and NOB concurrently displayed increased apoptotic signals and considerable ROS generation. NAR + NOB treatment in A549 cells resulted in the inhibition of PI3K/AKT/mTOR, blocking the formation of proteins that govern proliferation and cell cycle. To the current understanding, this is the first research to show that naringin and nobiletin interact to target the PI3K/AKT/mTOR pathway in NSCLC cells. More in vivo experiments are needed to determine the extent to which the combination of therapies induces apoptosis before they can be used commercially.