title: Toosendanin Exerts an Anti-Cancer Effect in Glioblastoma by Inducing Estrogen Receptor β- and p53-Mediated Apoptosis.
abstract: Glioblastoma (GBM) is the most common primary brain tumor with median survival of approximately one year. This dismal poor prognosis is due to resistance to currently available chemotherapeutics; therefore, new cytotoxic agents are urgently needed. In the present study, we reported the cytotoxicity of toosendanin (TSN) in the GBM U87 and C6 cell lines in vitro and in vivo. By using the MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide) assay, flow cytometry analysis, and Western blot, we found that TSN inhibited U87 and C6 cell proliferation and induced apoptosis at a concentration as low as 10 nM. Administration of TSN also reduced tumor burden in a xenograft model of athymic nude mice. Pharmacological and molecular studies suggested that estrogen receptor β (ERβ) and p53 were prominent targets for TSN. GBM cell apoptosis induced by TSN was a stepwise biological event involving the upregulation of ERβ and contextual activation of functional p53. Collectively, our study indicates, for the first time, that TSN is a candidate of novel anti-cancer drugs for GBM. Furthermore, ERβ and p53 could act as predictive biomarkers for the sensitivity of cancer to TSN.
authors.affiliation: Department of Traditional Chinese Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. caoliang402@fmmu.edu.cn.
authors.forename: Liang
authors.initials: L
authors.lastname: Cao
authors.affiliation: Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an 710032, China. qudingd@hotmail.com.
authors.forename: Dingding
authors.initials: D
authors.lastname: Qu
authors.affiliation: Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an 710032, China. pfkwhuan@163.com.
authors.forename: Huan
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Traditional Chinese Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. zhangsha@fmmu.edu.cn.
authors.forename: Sha
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Traditional Chinese Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. jiacm2014@sina.com.
authors.forename: Chenming
authors.initials: C
authors.lastname: Jia
authors.affiliation: Department of Acupuncture, Shaanxi Hospital of Traditional Chinese Medicine, Xi'an 710032, China. stone_x0319@163.com.
authors.forename: Zixuan
authors.initials: Z
authors.lastname: Shi
authors.affiliation: Department of Traditional Chinese Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. zongren@fmmu.edu.cn.
authors.forename: Zongren
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an 710032, China. biozhangj@fmmu.edu.cn.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Traditional Chinese Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. jingma@fmmu.edu.cn.
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008819:Mice, Nude; D008517:Phytotherapy / Q000379:methods; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034622:RNA Interference; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D014315:Triterpenes
chemical_list: D000970:Antineoplastic Agents; D004365:Drugs, Chinese Herbal; D047629:Estrogen Receptor beta; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C036454:toosendanin; D014315:Triterpenes
keywords: apoptosis; estrogen receptor β; glioblastoma; p53; toosendanin