title: Paris saponin II inhibits human ovarian cancer cell-induced angiogenesis by modulating NF-κB signaling.
abstract: The clinical applications of Rhizoma paridis in traditional Chinese medicine are well known. However, the therapeutic potential of Rhizoma paridis and its active component such as Paris saponin I (polyphyllin D) and Paris saponin II (PSII) (formosanin C) in cancer treatments have not yet been fully explored. Recent studies have demonstrated that PSII and chemoagents exhibit comparable inhibitory affects against human ovarian cancer cell growth. Since NF-κB, a ubiquitous transcription factor that plays an important role in cancer biology, is often associated with gynecological cancers, in the present study, we evaluated the possibility that PSII modulates NF-κB activity and VEGF-mediated angiogenesis and elucidated the molecular mechanisms underlying such effects. We assessed the effects of PSII on NF-κB activity in SKOV3 tumor cells and on tumor cell induced-angiogenesis using standardized angiogenesis in vitro, ex vivo and in vivo assays, western blot analysis and kinase assay. We also assessed the effect of the super-engineered repressor of IĸBα and its effect, in combination with PSII treatment on tumor growth and angiogenesis in xenograft athymic mouse models of ovarian cancer (SKOV3 and SKOV3/mutant IĸBα cells) using color Doppler ultrasound and traditional immunohistochemistry. We showed that PSII suppressed NF-κB activation as a result of the reduction in IKKβ kinase activity on its substrate IκBα and the expression of IKKβ. Compromising NF-κB activation reduced the expression of NF-κB-downstream targets such as VEGF, Bcl-2 and Bcl-xL. Such inhibitory effects at molecular levels appear to compromise tumor growth and angiogenesis. Most importantly, the combination of PSII treatment and constitutive repression of IĸBα activity exhibited marked inhibitory effects against human ovarian cancer cell growth in a xenograft mouse model of ovarian cancer. For the first time, we provide evidence showing that PSII potently inhibits angiogenesis and the growth of human ovarian cancer by suppressing NF-κB signaling.
authors.affiliation: Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Mei
authors.initials: M
authors.lastname: Yang
authors.affiliation: Department of Pathology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Juan
authors.initials: J
authors.lastname: Zou
authors.affiliation: Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Shanling
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: He
authors.initials: H
authors.lastname: Wang
authors.affiliation: West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Peng
authors.initials: P
authors.lastname: Bai
authors.affiliation: Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Xue
authors.initials: X
authors.lastname: Xiao
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004144:Diosgenin / Q000031:analogs & derivatives; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016328:NF-kappa B / Q000187:drug effects* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D012503:Saponins / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D016328:NF-kappa B; D012503:Saponins; C067584:formosanin C; D004144:Diosgenin