Identifying molecular targets of Aspiletrein-derived steroidal saponins in lung cancer using network pharmacology and molecular docking-based assessments

Abstract

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.

Preclinical Characterization of 22-(4′-Pyridinecarbonyl) Jorunnamycin A against Lung Cancer Cell Invasion and Angiogenesis via AKT/mTOR Signaling

“…A great negative energy value indicates better ligand-binding properties. , This suggests that 22-(4′-py)-JA may exert a more pronounced suppressive effect on AKT activation. Furthermore, the complex formed by 22-(4′-py)-JA and AKT demonstrated less fluctuation in the RMSD value throughout the 100 ns stimulation, indicating a stable interaction between the compound and protein target. , The investigation of the interaction between AKT and 22-(4′-py)-JA in an in vitro setting would indeed provide further support for our findings. Collectively, the present study provided crucial preclinical evidence of the antimetastatic activity and molecular mechanism of 22-(4′-py)-JA in NSCLC.…”

Comprehensive review of Bcl‐2 family proteins in cancer apoptosis: Therapeutic strategies and promising updates of natural bioactive compounds and small molecules

“…The activated MAPK/ERK pathway is a critical factor in regulating cell survival (Iksen et al, 2022). In lung cancer cells, epidermal growth factor-induced overexpression of MAPK/ERK leads to increased Bcl-2 levels, reducing the cell death rate and increasing cell viability.…”

“…The molecular mechanism was identified to be associated with elevated intracellular ROS and activation of AMPK signaling (Witayateeraporn et al, 2022). Network pharmacology analysis also revealed that STAT3 is a target of these compounds in regulating apoptosis (Iksen et al, 2023).…”

“…Aspiletrein A, a steroidal saponin found in Aspidistra letreae , has significant anticancer effects, particularly in lung cancer (Ho et al, 2020; Iksen et al, 2023; Nguyen et al, 2021). In vitro experiments revealed that aspiletrein A induced apoptosis in a dose‐dependent manner (Witayateeraporn et al, 2022).…”

Steroidal Saponins: Naturally Occurring Compounds as Inhibitors of the Hallmarks of Cancer

“…Aspiletreins A, B, and C have been tested against H460, H23, A549, LU-1, HeLa, MDA-MB-231, HepG2, and MKN-7 human cancer cell lines, providing promising anti-proliferative effects that were evaluated by SRB and MTT assays [22,24]. Iksen et al ( 2023) investigated the molecular mechanisms by which these steroidal saponins exert their anti-cancer properties on NSCLC using in silico approaches such as molecular docking and network pharmacology analysis [23]. The findings indicated that Aspiletreins A, B, and C primarily target STAT3 in its phosphorylated state, which is commonly observed in lung adenocarcinomas.…”