title: Paris polyphylla Suppresses Proliferation and Vasculogenic Mimicry of Human Osteosarcoma Cells and Inhibits Tumor Growth In Vivo.
abstract: Paris polyphylla, a traditional antipyretic-detoxicate chinese medicinal herb, has been applied extensively in cancer treatments for nearly 2000 years. The purpose of the present study is to evaluate the potential anti-osteosarcoma effects of Paris polyphylla ethanol extract (PPEE) and to investigate its underlying mechanisms. The antiproliferation activity of PPEE was tested on 143B, MG-63, U-2 OS and hFOB1.19 cells using MTT assay. The pro-apoptotic and cell cycle arrest effects of PPEE were confirmed by Hoechst 33342 staining and flow cytometry. The antimigratory, anti-invasive and antivasculogenic mimicry (VM) effects of PPEE were investigated by wound healing, Transwell and 3D culture assays. Mouse xenograft model was used to examine its anti-osteosarcoma efficacy in vivo. Hematologic profiles and hepatorenal functions were evaluated to assess the toxicity of PPEE. PPEE evidently suppressed cell proliferation of 143B, MG-63 and U-2 OS with IC50 values of 10-60[Formula: see text][Formula: see text]g/mL, but showed little cytotoxicity against normal osteoblastic cell. PPEE promoted apoptosis in 143B cell via caspase activation, increased Bax/Bcl-2 ratio and PARP cleavage. It also induced G2/M phase arrest associated with elevated phosphorylation of CDK1, Cdc25C, Chk2 and down-regulation of cyclin B1, CDK1, Cdc25C expression. Additionally, PPEE inhibited 143B cell migration, invasion and VM formation at noncytotoxic concentrations through decreasing the expression of FAK, Mig-7, MMP2 and MMP9. Finally, daily oral administration of PPEE for four weeks exhibits potent antitumor and anti-VM activity in 143B xenograft model with low toxicity. Taken together, these findings demonstrated PPEE possesses anti-osteosarcoma and anti-VM activity in vitro and in vivo, and therefore is a potential candidate for osteosarcoma treatment.
authors.affiliation: * Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, Jiangsu Province, P.R. China.|† Laboratory of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, Jiangsu Province, P.R. China.
authors.forename: Nan
authors.initials: N
authors.lastname: Yao
authors.affiliation: ‡ Department of Orthopaedics, Zhongda Hospital, Southeast University, Nanjing 210009, Jiangsu Province, P.R. China.
authors.forename: Ke
authors.initials: K
authors.lastname: Ren
authors.affiliation: § Department of Orthopedics, The Third Affiliated Hospital of Soochow University, (The First People's Hospital of Changzhou), Changzhou City 213003, Jiangsu Province P.R. China.
authors.forename: Yimin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: * Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, Jiangsu Province, P.R. China.|† Laboratory of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, Jiangsu Province, P.R. China.
authors.forename: Qiaomei
authors.initials: Q
authors.lastname: Jin
authors.affiliation: ¶ Nanjing Biopharmaceutical Innovation Platform Company Limited, Nanjing 210032, Jiangsu Province, P.R. China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Lu
authors.affiliation: * Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, Jiangsu Province, P.R. China.|† Laboratory of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, Jiangsu Province, P.R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.affiliation: * Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, Jiangsu Province, P.R. China.|† Laboratory of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, Jiangsu Province, P.R. China.
authors.forename: Cuihua
authors.initials: C
authors.lastname: Jiang
authors.affiliation: * Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, Jiangsu Province, P.R. China.|† Laboratory of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, Jiangsu Province, P.R. China.
authors.forename: Dongjian
authors.initials: D
authors.lastname: Zhang
authors.affiliation: ‡ Department of Orthopaedics, Zhongda Hospital, Southeast University, Nanjing 210009, Jiangsu Province, P.R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.affiliation: ‡ Department of Orthopaedics, Zhongda Hospital, Southeast University, Nanjing 210009, Jiangsu Province, P.R. China.
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.affiliation: * Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, Jiangsu Province, P.R. China.|† Laboratory of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, Jiangsu Province, P.R. China.
authors.forename: Jiege
authors.initials: J
authors.lastname: Huo
authors.affiliation: ∥ Jinling Hospital, Department of Orthopedics, Nanjing University, School of Medicine, Nanjing 210002, Jiangsu Province, P.R. China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: * Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, Jiangsu Province, P.R. China.|† Laboratory of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, Jiangsu Province, P.R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness / Q000473:pathology; D009368:Neoplasm Transplantation; D012516:Osteosarcoma / Q000188:drug therapy* / Q000473:pathology*; D008517:Phytotherapy; D014407:Tumor Cells, Cultured
chemical_list: D004365:Drugs, Chinese Herbal
keywords: Apoptosis; Cell Cycle; Osteosarcoma; Paris polyphylla; Vasculogenic Mimicry