A network pharmacology-based approach to explore mechanism of kaempferol-7-O-neohesperidoside against prostate cancer

Aim To explore the effect of kaempferol-7-O-neohesperidoside (K7ON) against prostate cancer (PCa) and the underlying mechanism. Methods The effect of K7ON on the proliferation of PCa cell lines PC3, DU145, C4-2 and LNCaP was detected using CCK8 assay. The effect of K7ON on migration ability of DU145 cells was determined by wound healing assay. The targets of K7ON and PCa were screened from SuperPred and other databases. The common targets both related to K7ON and PCa were obtained from the Venny online platform; a protein-protein interaction network (PPI) was constructed by the String and Cytoscape. Meanwhile, the GO and KEGG functional enrichment were analyzed by David database. Then, a “drug-target-disease-pathway” network model was constructed. Cell cycle of PCa cells treated with K7ON was analyzed by flow cytometry. The expressions of cycle-associated proteins including Skp2, p27 and p21 protein were detected by Western blot. Molecular docking between Skp2 and K7ON was conducted by Sybyl X2.0. Results K7ON significantly inhibited the proliferation and migration of PCa cells. A total number of 34 drug-disease intersection targets were screened. The String results showed that Skp2 and p27, among the common targets, were the key targets of K7ON for PCa treatment. Furthermore, GO and KEGG functional enrichment indicated that the mechanism was mainly related to the cell cycle. Flow cytometry showed that K7ON treatment induced cell cycle arrest at the S phase. Compared with the control group, the protein expression level of Skp2 was significantly down-regulated, while the protein expression levels of p27 and p21 were up-regulated. The network molecular docking indicated that the ligand K7ON had a good binding ability with the receptor Skp2. Conclusions K7ON could inhibit the proliferation and migration of PCa cells, block the cell cycle in the S phase, which may be related to the regulation of cell cycle through the Skp2-p27/p21 signaling pathway