title: Ilexgenin A exerts anti-inflammation and anti-angiogenesis effects through inhibition of STAT3 and PI3K pathways and exhibits synergistic effects with Sorafenib on hepatoma growth.
abstract: Recently, we reported that Ilexgenin A exhibits anti-cancer activities and induces cell arrest. Here, we investigated the effect of Ilexgenin A on the inflammation, angiogenesis and tumor growth of hepatocellular carcinoma (HCC). Our current study revealed that Ilexgenin A significantly inhibited the inflammatory cytokines TNF-α and IL-6 levels and downregulated pro-angiogenic factor VEGF production and transcription in HepG2 cells. The underlying mechanism for Ilexgenin A effects appears to be through inhibiting STAT3 and PI3K pathways. Furthermore, we found that not only Ilexgenin A inhibited STAT3 and PI3K pathways in HepG2 cells but also blocked these signaling pathways in HUVECs. Most importantly, by employing two HCC xenografts models - HepG2 and H22, we showed that Ilexgenin A reduced tumor growth and exhibited synergy effect with Sorafenib. ELISA assay, histological analysis and immunohistochemistry examination revealed that the expression of VEGF and MVD was significantly decreased after the treatment with Ilexgenin A and the combination. Moreover, Ilexgenin A could enhance caspase-3/7 activity in vitro and transmission electron microscope indicated that the combination induced evident apoptosis of tumor cells and caused the structural changes of mitochondria in vivo. Although no apparent adverse effects occurred during the treatment period, Sorafenib monotherapy elicited hepatotoxicity for specific expression in the increased level of AST and the ratio of AST/ALT. However, the combination could remedy this adverse effect. In conclusion, the results described in the present study identifies Ilexgenin A as a promising therapeutic candidate that modulates inflammation, angiogenesis, and HCC growth.
authors.affiliation: Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu, PR China; College of Medicine, Yangzhou University, Yangzhou 225001, Jiangsu, PR China; Institute of Pharmacology and Toxicology, Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang 222000, Jiangsu, PR China.
authors.forename: Hao
authors.initials: H
authors.lastname: Yang
authors.affiliation: Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu, PR China; College of Medicine, Yangzhou University, Yangzhou 225001, Jiangsu, PR China.
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.affiliation: Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu, PR China.
authors.forename: Jin-Hong
authors.initials: JH
authors.lastname: Fan
authors.affiliation: Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu, PR China.
authors.forename: Ya-Qi
authors.initials: YQ
authors.lastname: Zhang
authors.affiliation: Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu, PR China.
authors.forename: Jun-Xian
authors.initials: JX
authors.lastname: Zhao
authors.affiliation: Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu, PR China; Chinese Medicine Hospital of Yangzhou City, Yangzhou 225009, Jiangsu, PR China.
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Dai
authors.affiliation: Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu, PR China; College of Medicine, Yangzhou University, Yangzhou 225001, Jiangsu, PR China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu, PR China; College of Medicine, Yangzhou University, Yangzhou 225001, Jiangsu, PR China.
authors.forename: Yan-Jun
authors.initials: YJ
authors.lastname: Shen
authors.affiliation: Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu, PR China.
authors.forename: Chang
authors.initials: C
authors.lastname: Liu
authors.affiliation: Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu, PR China; Chinese Medicine Hospital of Yangzhou City, Yangzhou 225009, Jiangsu, PR China. Electronic address: zyykjc@sina.com.
authors.forename: Wei-Dong
authors.initials: WD
authors.lastname: Sun
authors.affiliation: Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu, PR China; College of Medicine, Yangzhou University, Yangzhou 225001, Jiangsu, PR China. Electronic address: ysun@yzu.edu.cn.
authors.forename: Yun
authors.initials: Y
authors.lastname: Sun
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D000077157:Sorafenib; D014315:Triterpenes / Q000494:pharmacology*
chemical_list: D020533:Angiogenesis Inhibitors; D000893:Anti-Inflammatory Agents; D010671:Phenylurea Compounds; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014315:Triterpenes; C468850:ilexgenin A; D009536:Niacinamide; D000077157:Sorafenib; D019869:Phosphatidylinositol 3-Kinases
keywords: Angiogenesis; Ilexgenin A; PI3K; STAT3; Sorafenib; Synergy effect