Lung cancer is one of the leading cancers and causes of cancer-related deaths worldwide. Due to its high prevalence and mortality rate, its clinical management remains a significant challenge. Previously, the in vitro anticancer activity of Aspiletrein A, a steroid and a saponin from Aspidistra letreae, against non-small cell lung cancer (NSCLC) cells was reported. However, the anticancer molecular mechanism of other Aspiletreins from A. letreae remains unknown. Using in silico network pharmacology approaches, the targets of Aspiletreins were predicted using the Swiss Target Prediction database. In addition, key mediators in NSCLC were obtained from the Genetic databases. The compound-target interacting networks were constructed using the STRING database and Cytoscape, uncovering potential targets, including STAT3, VEGFA, HSP90AA1, FGF2, and IL2. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis demonstrated that several pathways were highly relevant to cancer pathogenesis. Additionally, molecular docking and molecular dynamic analyses revealed the interaction between key identified targets and Aspiletreins, including hydrogen bonding and Van der Waals interaction. This study provides potential targets of Aspiletreins in NSCLC, and its approach of integrating network pharmacology, bioinformatics, and molecular docking is a powerful tool for investigating the mechanism of new drug targets on a specific disease.
Lung cancer remains a leading cause of death in cancer patients, and deregulation of apoptosis is a serious concern in clinical practice, even though therapeutic intervention has been greatly improved. Plants are a versatile source of biologically active compounds for anticancer drug discovery, and aspiletrein A (AA) is a steroidal saponin isolated from Aspidistra letreae that has a potent cytotoxic effect on various cancer cell lines. In this study, we investigated and determined the underlying molecular mechanism by which AA induces apoptosis. AA strongly induced apoptosis in NSCLC cells by mediating ROS generation and thereby activating AMP-activated protein kinase (AMPK) signaling. Consequently, downstream signaling and levels of phosphorylated mTOR and Bcl-2 were significantly decreased. Pretreatment with either an antioxidant, N-acetylcysteine, or an AMPK inhibitor, compound C, could reverse the apoptosis-inducing effect and counteract the effect of AA on the AMPK signaling pathway. Decreased levels of Bcl-2 were due to AA-mediating Bcl-2 degradation via a ROS/AMPK/mTOR axis-dependent proteasomal mechanism. Consistently, the apoptotic-inducing effect of AA was also observed in patient-derived malignant lung cancer cells, and it suppressed an in vitro 3D-tumorigenesis. This study identified the underlying mechanism of AA on lung cancer apoptosis, thereby facilitating potential research and development of this compound for further clinical implications.
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