Elucidating the mechanism of action of Isobavachalcone induced autophagy and apoptosis in non-small cell lung cancer by network pharmacology and experimental validation methods

Luyao Wang; Ziqiang Wang; Yuhan Ni; Xue Wang; Tingting Zhang; Mengling Hu; Chaoqun Lian; Xiaojing Wang; Jing Zhang

doi:10.1016/j.gene.2024.148474

Elucidating the mechanism of action of Isobavachalcone induced autophagy and apoptosis in non-small cell lung cancer by network pharmacology and experimental validation methods

Gene. 2024 Apr 24:918:148474. doi: 10.1016/j.gene.2024.148474. Online ahead of print.

Authors

Luyao Wang¹, Ziqiang Wang², Yuhan Ni³, Xue Wang⁴, Tingting Zhang⁵, Mengling Hu⁵, Chaoqun Lian⁶, Xiaojing Wang⁷, Jing Zhang⁸

Affiliations

¹ Anhui Province Key Laboratory of Clinical and Preclinical Research in Respiratory Disease, Molecular Diagnosis Center, Department of Pulmonary and Critical Care Medicine, First Affiliated Hospital of Bengbu Medical College, Bengbu 233030, China; Department of Genetics, School of Life Sciences, Bengbu Medical College, Bengbu 233030, China.
² Research Center of Clinical Laboratory Science, Bengbu Medical College, Bengbu 233030, China.
³ Anhui Province Key Laboratory of Clinical and Preclinical Research in Respiratory Disease, Molecular Diagnosis Center, Department of Pulmonary and Critical Care Medicine, First Affiliated Hospital of Bengbu Medical College, Bengbu 233030, China.
⁴ Digestive Department, Xi'an Fifth Hospital, Xi'an 710000, China.
⁵ Department of Genetics, School of Life Sciences, Bengbu Medical College, Bengbu 233030, China.
⁶ Research Center of Clinical Laboratory Science, Bengbu Medical College, Bengbu 233030, China. Electronic address: lianchaoqun@bbmc.edu.cn.
⁷ Anhui Province Key Laboratory of Clinical and Preclinical Research in Respiratory Disease, Molecular Diagnosis Center, Department of Pulmonary and Critical Care Medicine, First Affiliated Hospital of Bengbu Medical College, Bengbu 233030, China; Joint Research Center for Regional Diseases of IHM, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233030, China. Electronic address: wangxiaojing8888@163.com.
⁸ Department of Genetics, School of Life Sciences, Bengbu Medical College, Bengbu 233030, China. Electronic address: jade.zhangjing@bbmc.edu.cn.

PMID: 38670393
DOI: 10.1016/j.gene.2024.148474

Abstract

Background: Lung cancer is the leading cause of cancer deaths, and non-small cell lung cancer (NSCLC) accounts for the majority of lung cancer-related mortality. In recent years, there have been numerous treatments for non-small cell lung cancer, but the cure and survival rates are still extremely low. Isobavachalcone (IBC) belongs to the chalcone component of the traditional Chinese medicine Psoralea corylifolia L., and is a unique Protein kinase B (AKT) pathway inhibitor with significant anticancer effects. Previous studies have shown that IBC possess a variety of biological properties, including anti-cancer, anti-inflammatory, and antioxidant properties. This study focused on the use of network pharmacology analysis, molecular docking technology and experimental validation to elucidate the potential mechanisms of IBC for the treatment of NSCLC.

Methods: Screening key genes and pathways of IBC action in NSCLC using network pharmacology. The IBC target genes were from The Encyclopedia of Traditional Chinese Medicine (ETCM) and BATMAN-TCM databases, the NSCLC target genes were from GeneCards, Online Mendelian Inheritance in Man (OMIM) and The Therapeutic Target database (TTD) databases, both of which were taken as intersecting genes for protein-protein interaction network analysis and enrichment analysis, and the binding energies of the compounds to the core targets were further verified by molecular docking. Cell lines in vitro experiments were then performed to further unravel the mechanism of IBC for NSCLC.

Results: A total of 279 potential targets were retrieved by searching the intersection of IBC and NSCLC targets. Protein-protein interaction (PPI) network analysis indicated that 6 targets, including AKT1, RXRA, NCOA1, RXRB, RARA, PPARG were hub genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis suggested that IBC treatment of NSCLC mainly involves steroid binding, transcription factor activity, Pathways in cancer, cAMP signaling pathway, Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway. Among them, the AMPK signaling pathway, which contained the largest number of enriched genes, may play a greater role in the treatment of NSCLC. Then, the results of in vitro experiment indicated that IBC could inhibit proliferation of NSCLC cells and induce cell autophagy and apoptosis. The results also showed that IBC could increase the protein expression of AMPK and decrease the protein expression of AKT and mammalian target of rapamycin (mTOR), suggesting that IBC can treat NSCLC by inducing cellular autophagy and apoptosis as well as modulating AMPK and AKT signaling pathways.

Conclusions: In summary, this study provided a new insight into the protective mechanism of IBC against NSCLC through network pharmacology and experimental validation.

Keywords: Apoptosis; Autophagy; Isobavachalcone; Network pharmacology; Non-small cell lung cancer.