Cao Liang, Qu Dingding, Wang Huan, Zhang Sha, Jia Chenming, Shi Zixuan, Wang Zongren, Zhang Jian, Ma Jing
Department of Traditional Chinese Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an 710032, China.
Int J Mol Sci. 2016 Nov 18;17(11):1928. doi: 10.3390/ijms17111928.
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--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.
胶质母细胞瘤（GBM）是最常见的原发性脑肿瘤，中位生存期约为一年。这种预后不佳是由于对目前可用的化疗药物产生耐药性；因此，迫切需要新的细胞毒性药物。在本研究中，我们报道了川楝素（TSN）在体外和体内对GBM U87和C6细胞系的细胞毒性。通过使用MTT（3-(4,5-二甲基-2-噻唑基)-2,5-二苯基-2-溴化四氮唑）试验、流式细胞术分析和蛋白质印迹法，我们发现TSN在低至10 nM的浓度下就能抑制U87和C6细胞增殖并诱导细胞凋亡。给予TSN还能减轻无胸腺裸鼠异种移植模型中的肿瘤负担。药理学和分子研究表明，雌激素受体β（ERβ）和p53是TSN的主要靶点。TSN诱导的GBM细胞凋亡是一个逐步的生物学事件，涉及ERβ的上调和功能性p53的背景激活。总的来说，我们的研究首次表明，TSN是一种用于GBM的新型抗癌药物候选物。此外，ERβ和p53可作为癌症对TSN敏感性的预测生物标志物。
