Journal of Southern Medical University

Journal of Southern Medical University ›› 2023, Vol. 43 ›› Issue (7): 1051-1062.doi: 10.12122/j.issn.1673-4254.2023.07.01

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Analysis of therapeutic mechanism of Liushen Wan against colitis-associated colorectal cancer based on network pharmacology and validation in mice

ZHANG Xuefang, CHEN Yanhua, LI Zongheng, SHANG Jing, YUAN Zeting, DENG Wanli, LUO Ying, HAN Na, YIN Peihao, YIN Jun   

  1. School of Traditional Chinese Medicine, Shengyang Pharmaceutical University, Benxi 117004, China; Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine; Interventional Cancer Institute of Chinese Integrative Medicine, Shanghai Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China; Clinical Laboratory, Shanghai Changning Maternity and Infant Health Hospital, Shanghai 200000, China
  • Online:2023-07-20 Published:2023-07-20

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Abstract: Objective To explore the therapeutic mechanism of Liushen Wan (LSW) against colitis-associated colorectal cancer (CAC) by network pharmacology. Methods TCMSP, BATMAN-TCM, CNKI, PubMed, Genecards, OMIM, and TTD databases were used to obtain the related targets of LSW and CAC. The common targets of LSW and CAC were obtained using Venny online website. The PPI network was constructed using Cytoscape 3.8.2 to screen the core targets of LSW in the treatment of CAC. GO and KEGG enrichment analysis were conducted using DAVID database. The therapeutic effect of LSW on CAC was evaluated in a C57BL/6J mouse model of AOM/DSS-induced CAC by observing the changes in body weight, disease activity index, colon length, and size and number of the tumor. HE staining and RT-qPCR were used to analyze the effect of LSW on inflammatory mediators. Immunohistochemistry and TUNEL staining were used to evaluate the effect of LSW on the proliferation and apoptosis of AOM/DSS-treated colon tumor cells. Immunohistochemistry and Western blotting were used to detect the effects of LSW on the expression of TLR4 proteins in CAC mice. Results Network pharmacology analysis identified 69 common targets of LSW and CAC, and 33 hub targets were screened in the PPI network. KEGG pathway enrichment analysis suggested that the effect of LSW on CAC was mediated by the Toll-like receptor signaling pathway. In the mouse model of AOM/DSS-induced CAC, LSW significantly inhibited colitis-associated tumorigenesis, reduced tumor number and tumor load (P<0.05), obviously improved histopathological changes in the colon, downregulated the mRNA levels of pro-inflammatory cytokines, and inhibited the proliferation (P<0.01) and promoted apoptosis of colon tumor cells (P<0.001). LSW also significantly decreased TLR4 protein expression in the colon tissue (P<0.05). Conclusion LSW can inhibit CAC in mice possibly by regulating the expression of TLR4 to reduce intestinal inflammation, inhibit colon tumor cell proliferation and promote their apoptosis.

Key words: Liushen Wan; network pharmacology; colitis-associated colorectal cancer; Toll-like receptor signaling pathway; TLR4