Interpretation of the absorbed constituents and pharmacological effect of Spica Schizonepetae extract on non-small cell lung cancer.

Abstract

As a traditional Chinese medicine (TCM) with a usage history of over 2,000 years in China, Spica Schizonepetae possesses definite clinical activity in the treatment of non-small cell lung cancer (NSCLC). However, its active ingredients and mechanism of action remain unclear at present. The further exploration of its active components and underlying mechanism will provide a basis for the development of candidate anti-tumor drugs. Our previous study explored the chemical constituents of Spica Schizonepetae extract (SSE). On this basis, molecular networking technology was applied in analyzing the QTOF-MS/MS data of rat plasma after intragastric administration of SSE using the GNPS database platform. A total of 26 components were found, including 9 proterotype components and 17 metabolites, which revealed the potential active ingredients of SSE. Later, the Lewis lung cancer mouse model was established, and the inhibition rate and histopathological sections were used as the indicators to investigate the anti-tumor effect of SSE, whereas the body weight, survival rate, thymus index and spleen index served as the indicators to explore the pharmacological effects of SSE on improving mouse immunity. The results showed that SSE had comparable anti-tumor efficacy to cisplatin, which enhanced the immunity, improved the quality of life, and extended the survival time of lung cancer mice. Furthermore, human A549 lung tumor cells were selected to explore the mechanism of SSE in treating NSCLC based on cell metabonomics. After data mining by the MPP software, 23 differential endogenous metabolites were identified between SSE and tumor groups. Moreover, results of pathway enrichment analysis using the MetaboAnalyst 4.0 software indicated that these metabolites were mainly enriched in four metabolic pathways (p < 0.1). By adopting the network pharmacology method, the metabolic pathways discovered by cell metabolomics were verified against the ChEMBL, STITCH, UniProt and TCGA databases, and differences in the underlying mechanism between cells and humans were found. It was proved that SSE affected the metabolism of purine, arachidonic acid and histidine to exert the anti-tumor efficacy. Furthermore, the multi-target, multi-pathway, and immunoenhancement mechanism of SSE in anti-tumor treatment was revealed, which provided a scientific basis for new drug development and the rational application of Spica Schizonepetae in clinic.