ETHNOPHARMACOLOGICAL RELEVANCE

Lichong decoction, a classic Chinese herbal formula, has been used to treat gynaecological diseases and abdominal masses. According to the principle of syndrome differentiation to treat tumours in TCM combined with the pathogenesis of gastric carcinoma, we added some Chinese herbs which have the pharmaceutical effect of clearing heat antitoxicants and resolving masses to form a modified Lichong decoction (MLCD) formula for the treatment of gastric cancer. Currently, the anti-gastric cancer effects and mechanism of MLCD have not been reported in laboratory data; however, clinical practice has found that it has a certain therapeutic effect.

AIM OF THE STUDY

Metabolomics, network pharmacology, and pharmacological verification were used to investigate the anti-gastric cancer effects and molecular mechanisms of action of MLCD.

MATERIALS AND METHODS

The primary components of the MLCD were identified using UPLC-Q/TOF-MS combined with the TCMSP database. The anti-gastric cancer activity was monitored in transplanted nude mice treated with MLCD (150, 300, and 600 mg/kg) through gavage for 4 weeks, and the anti-gastric cancer mechanism of MLCD was analysed using network pharmacology, metabolomics, and molecular docking. Pharmacological experiments were performed to elucidate the potential mechanism of action of MLCD as an anti-gastric cancer agent. Weight change, organ index, and serum biochemistry of cancer-bearing mice were assessed to preliminarily evaluate MLCD toxicity.

RESULTS

Sixteen components were identified using UPLC-Q/TOF-MS. The pharmacological effects confirmed that MLCD could inhibit growth, induce apoptosis of transplanted tumours, and arrest the cell cycle in mouse tissues at the G2/M phase. Network pharmacological analysis revealed multiple targets and signalling pathways involved in the treatment of gastric cancer using MCLD. Metabolomic analysis has shown that multiple metabolites and metabolic pathways participate in the treatment of gastric cancer using MCLD. More importantly, the results of both network pharmacology and metabolomics highlighted the importance of the PI3k/Akt pathway, as a key route through which MLCD exerts its anti-gastric cancer effects. In addition, the molecular docking results confirmed that the core components of MLCD exhibited a strong affinity for AKT1 targets. Gene and protein tests revealed that MLCD reduced the protein levels of p-Akt and p-FoxO3a, decreased the gene expression of FoxO3a, decreased the gene and protein expression of Bcl-2, Cyclin B1 and CDK1, and increased the expression of Bim and Bax in subcutaneously xenografted tumours of nude mice. MLCD had little effect on the levels of ALT, AST, Cr, and BUN, as well as the body weight and indices of the liver, kidney, and spleen in cancer-bearing mice.

CONCLUSIONS

This study evaluated the pharmacological effects of MLCD on gastric cancer. These results suggest that MLCD can exert an anti-gastric cancer effects through multiple targets and pathways and that the PI3k/Akt pathway is an important pathway in the regulation of proliferation, cell cycle, and apoptosis in gastric cancer. The toxic effects of MLCD on tumour-bearing mice were indistinctively observed after continuous administration for 4 weeks.