Modulatory effects of Xihuang Pill on lung cancer treatment by an integrative approach

Lung cancer has a rapidly increasing incidence and remains the highest ranked cancer in terms of mortality worldwide. Xihuang Pill(XHW), a famous four-herb traditional Chinese formulation, has been used to treat lung cancer in China for more than 100 years. It is usually prescribed as a complementary and alternative medicine for cancer therapy. However, the main active ingredients of XHW that treat lung cancer and their regulatory effects remain unclear. Here, we revealed modulatory effects effects of XHW on lung cancer in a mouse model of Lewis lung cancer (LLC) by a comprehensive strategy combining network pharmacology with metabolomics. The results demonstrated that XHW inhibited tumour growth in this model. Additionally, 11 differentially expressed metabolites were identified in the XHW group compared to those in the model group or normal group by untargeted metabolomics. They were enriched in amino acid-related metabolic pathways, and the top three pathways were phenylalanine metabolism; phenylalanine, tyrosine and tryptophan biosynthesis; and aminoacyl-tRNA biosynthesis. A total of 107 active components derived from Niuhuang, Shexiang, Ruxiang and Moyao, directly acted on 13 important targets (NR3C2, AKR1D1, MPO, PNP, NT5E, TAAR1, ADRB2, ADRB1, ADRA1A, ADRA2B, ADRA2A, MAOA and MAOB) to regulate 4 metabolites (L-phenylalanine, l-adrenaline, corticosterone and guanosine). Our results suggested that the key metabolites of XHW involved in the treatment of lung cancer were regulated by a multi-component and multi-target interaction network. This research elucidated the modulatory effect and therapeutic advantages of XHW treatment for lung tumours through an integrated approach.