title: Sprengerinin C exerts anti-tumorigenic effects in hepatocellular carcinoma via inhibition of proliferation and angiogenesis and induction of apoptosis.
abstract: The multi-targeted therapy for liver cancer has been considered as a novel strategy to fight hepatocellular carcinoma. In this study, we first found that sprengerinin C, a naturally derived compound strongly suppressed tumor angiogenesis in human umbilical vein endothelial cells. A mechanism study revealed that sprengerinin C blocked vascular endothelial growth factor receptor 2-dependent phosphoinositide 3-kinase/Akt/mTOR/matrix metalloproteinase and p38 MAPK/matrix metalloproteinase pathways, two major pathways for tumor angiogenesis. Moreover, sprengerinin C inhibited vascular endothelial growth factor release, a vital event for early angiogenesis response, from hypoxic HepG-2/BEL7402 cells by suppressing hypoxia-inducible factor-1α transcriptional activity. Furthermore, sprengerinin C induced HepG-2/BEL7402 cell apoptosis by activating NADPH oxidase/reactive oxygen species-dependent caspase apoptosis pathway and suppressed HepG-2/BEL7402 cell growth through p53-mediated G2/M-phase arrest. Sprengerinin C also showed a significant anti-tumor effect in the nude mouse xenograft model of human hepatocellular carcinoma. These results provide new insights into development of potent candidate compounds for liver cancer through affecting multiple tumor progression steps of angiogenesis, apoptosis and proliferation.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, PR China.
authors.forename: Ke-Wu
authors.initials: KW
authors.lastname: Zeng
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.forename: Xin
authors.initials: X
authors.lastname: Dong
authors.forename: Zhi-Zhong
authors.initials: ZZ
authors.lastname: Ma
authors.forename: Yong
authors.initials: Y
authors.lastname: Jiang
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Jin
authors.forename: Peng-Fei
authors.initials: PF
authors.lastname: Tu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000098:blood supply* / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008113:Liver Neoplasms / Q000098:blood supply* / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012503:Saponins / Q000494:pharmacology* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D012503:Saponins; D058570:TOR Serine-Threonine Kinases; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D048051:p38 Mitogen-Activated Protein Kinases; C497442:HIF1A protein, human; C588175:sprengerinin C
keywords: Angiogenesis; Apoptosis; Hepatocellular carcinoma; Proliferation; Sprengerinin C