Ibrutinib, a Bruton's tyrosine kinase inhibitor, exhibits antitumoral activity and induces autophagy in glioblastoma.
Ibrutinib, a Bruton's tyrosine kinase inhibitor, exhibits antitumoral activity and induces autophagy in glioblastoma.
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依鲁替尼 (Ibrutinib) 是一种布鲁顿氏酪氨酸激酶抑制剂，具有抗肿瘤活性并诱导胶质母细胞瘤自噬
DOI：
10.1186/s13046-017-0549-6
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发表时间：
2017-07-17
期刊：
影响因子：
--
通讯作者：
Zhao P
中科院分区：
文献类型：
--
作者：
Wang J;Liu X;Hong Y;Wang S;Chen P;Gu A;Guo X;Zhao P
胶质母细胞瘤（GBM）是成人中最常见和最具侵袭性的原发性脑肿瘤。伊布替尼是一种布鲁顿酪氨酸激酶（BTK）抑制剂，是一种新型抗肿瘤药物，用于治疗多种癌症。在这项研究中，我们的目的是确定伊鲁替尼对GBM的作用。通过使用细胞活力、集落形成和5-乙炔基-2 ′-脱氧尿苷（EdU）测定来确定细胞增殖。流式细胞仪检测细胞周期和细胞凋亡。通过伤口愈合试验和跨孔迁移试验评价细胞迁移能力。通过用Atg 7特异性小干扰RNA转染来敲低ATG 7表达。通过用表达组成型活性Akt（CA-Akt）的质粒转染细胞来实现活性Akt蛋白的过表达。透射电子显微镜检查细胞中自噬体的形成。免疫荧光和蛋白质印迹分析用于分析蛋白质表达。进行裸鼠中的肿瘤异种移植物和免疫组织化学以评价伊曲替尼对体内肿瘤生长的影响。在LN 229和U87细胞中，依鲁替尼抑制细胞增殖和迁移，并诱导细胞凋亡和自噬。活性Akt蛋白的过表达降低了伊匹尼诱导的自噬，而通过LY 294002处理抑制Akt增强了伊匹尼诱导的自噬。通过3-甲基腺嘌呤（3 MA）或Atg 7靶向小干扰RNA（si-Atg 7）特异性抑制自噬增强了伊曲替尼在体外和体内的抗GBM作用。我们的研究结果表明，伊曲替尼发挥了深刻的抗肿瘤作用，并通过Akt/mTOR信号通路诱导GBM细胞自噬。自噬抑制促进了伊布替尼在GBM中的抗肿瘤活性。我们的研究结果为抗癌药物与自噬抑制剂联合治疗恶性胶质瘤的作用提供了重要见解。本文的在线版本（doi：10.1186/s13046-017-0549-6）包含补充材料，可供授权用户使用。
Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. Ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, is a novel anticancer drug used for treating several types of cancers. In this study, we aimed to determine the role of ibrutinib on GBM. Cell proliferation was determined by using cell viability, colony formation, and 5-ethynyl-2′-deoxyuridine (EdU) assays. Cell cycle and cell apoptosis were analyzed by flow cytometry. Cell migratory ability was evaluated by wound healing assays and trans-well migration assays. ATG7 expression was knocked-down by transfection with Atg7-specific small interfering RNA. Overexpression of active Akt protein was achieved by transfecting the cells with a plasmid expressing constitutively active Akt (CA-Akt). Transmission electron microscopy was performed to examine the formation of autophagosomes in cells. Immunofluorescence and western blot analyses were used to analyze protein expression. Tumor xenografts in nude mice and immunohistochemistry were performed to evaluate the effect of ibrutinib on tumor growth in vivo. Ibrutinib inhibited cellular proliferation and migration, and induced apoptosis and autophagy in LN229 and U87 cells. Overexpression of the active Akt protein decreased ibrutinib-induced autophagy, while inhibiting Akt by LY294002 treatment enhanced ibrutinib-induced autophagy. Specific inhibition of autophagy by 3-methyladenine (3MA) or Atg7 targeting with small interfering RNA (si-Atg7) enhanced the anti-GBM effect of ibrutinib in vitro and in vivo. Our results indicate that ibrutinib exerts a profound antitumor effect and induces autophagy through Akt/mTOR signaling pathway in GBM cells. Autophagy inhibition promotes the antitumor activity of ibrutinib in GBM. Our findings provide important insights into the action of an anticancer agent combining with autophagy inhibitor for malignant glioma. The online version of this article (doi:10.1186/s13046-017-0549-6) contains supplementary material, which is available to authorized users.
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影响因子：
7.8
作者：
Degtyarev, Michael;De Maziere, Ann;Orr, Christine;Lin, Jie;Lee, Brian B.;Tien, Janet Y.;Prior, Wei W.;van Dijk, Suzanne;Wu, Hong;Gray, Daniel C.;Davis, David P.;Stern, Howard M.;Murray, Lesley J.;Hoeflich, Klaus P.;Klumperman, Judith;Friedman, Lori S.;Lin, Kui
通讯作者：
Lin, Kui
影响因子：
48
作者：
Jansen, Michael;Yip, Stephen;Louis, David N.
通讯作者：
Louis, David N.
影响因子：
56.9
作者：
Cohen, MS;Zhang, C;Taunton, J
通讯作者：
Taunton, J
影响因子：
5.6
作者：
Riemenschneider MJ;Reifenberger G
通讯作者：
Reifenberger G
影响因子：
3.6
作者：
Eimer, Sandrine;Belaud-Rotureau, Marc-Antoine;Belloc, Francis
通讯作者：
Belloc, Francis