The modulatory properties of Si Jun Zi Tang enhancing anticancer of gefitinib by an integrating approach

Lung cancer remains the leading cause of cancer death worldwide, and the current therapy seems to have reached a plateau due to toxicities and acquired resistance. Therefore, exploration of novel therapeutic avenues may be useful. Si Jun Zi Tang (SJZ), a four-herb Chinese medicine formula first described approximately one thousand years, is often prescribed for cancer patients as a complementary therapy. However, whether SJZ benefits cancer patients as well as the main active constituents and its regulatory mechanism in combination with anticancer drugs remains unknown. Here, we investigated the anti-lung cancer potency and underlying mechanisms of the combination of gefitinib plus SJZ in mice with Lewis lung carcinoma (LLC), using histopathology and an integrated strategy of metabolomics and network pharmacology. The results showed that SJZ significantly enhanced gefitinib suppressing tumor growth and inhibiting LLC metastasis in LLC-bearing mice. Furthermore, 9 potential metabolomics biomarkers that differentially expressed in the SJZ/gefitinib group compared to the SJZ group or gefitinib group were identified by untargeted metabolomics, mainly involved three pathways: tricarboxylic acid cycle, tyrosine and tryptophan biosynthesis metabolism and linoleic acid metabolism. Five active ingredients, kaempferol, ginsenoside Rf, caprylic acid, lauric acid and naringenin, acted directly on 9 targets and regulated 4 out of 9 metabolites. Our results indicated that SJZ enhanced the anti-lung cancer effects of gefitinib via the key targets ABCG2, ABCC1, ABAT, GSR, CYP1A2, ALOX5, CYP3A4, PLA2G1B and PLA2G2A and the key metabolites 2-oxoglutarate, taurocholic acid, oxidized glutathione and linoleic acid. This work illustrated the modulatory properties of SJZ, which enhanced the anticancer effects of gefitinib, using metabolomics and network pharmacology analyses, and provided insights into underlying the mechanism the active ingredients of SJZfor the treatment of lung cancer in combination with gefitinib.