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学科主题: 临床医学
题名:
Sulforaphane reverses chemo-resistance to temozolomide in glioblastoma cells by NF-kappa B-dependent pathway downregulating MGMT expression
作者: Lan, Fengming1; Yang, Yang2; Han, Jing3; Wu, Qiaoli4; Yu, Huiming5; Yue, Xiao4
关键词: glioblastoma ; sulforaphane ; temozolomide ; nuclear factor-kappa B ; O6-methylguanine-DNA methyltransferase
刊名: INTERNATIONAL JOURNAL OF ONCOLOGY
发表日期: 2016-02-01
DOI: 10.3892/ijo.2015.3271
卷: 48, 期:2, 页:559-568
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Oncology
研究领域[WOS]: Oncology
关键词[WOS]: DNA-DAMAGE ; INDUCED APOPTOSIS ; PROMOTER METHYLATION ; MALIGNANT GLIOMA ; CANCER-CELLS ; IN-VITRO ; INHIBITION ; ACTIVATION ; SURVIVAL ; GROWTH
英文摘要:

The survival benefits of patients with glioblastoma (GBM) remain unsatisfactory due to the intrinsic or acquired resistance to temozolomide (TMZ). We elucidated the mechanisms of sulforaphane (SFN) reverse TMZ resistance in TMZ-inducing cell lines by inhibiting nuclear factor-kappa B (NF-kappa B) transcriptional activity. TMZ-resistant cell lines (U87-R and U373-R) were generated by stepwise (6 months) exposure of parental cells to TMZ. Luciferase reporter assay, biochemical assays and subcutaneous tumor establishment were used to characterize the antitumor effect of SFN. MGMT expression and 50% inhibiting concentration (IC50) values of TMZ in GBM cell lines were assessed. Next, we established that U87-R and U373-R cells presenting high IC50 of TMZ, activated NF-kappa B transcription and significantly increased MGMT expression compared with untreated cells. Furthermore, we revealed that SFN could significantly suppress proliferation of TMZ-resistant GBM cells. In addition, SFN effectively inhibited activity of NF-kappa B signaling pathway and then reduced MGMT expression to reverse the chemo-resistance to TMZ in T98G, U87-R and U373-R cell lines. Sequential combination with TMZ synergistically inhibited survival capability and increased the induction of apoptosis in TMZ-resistant GBM cells. Finally, a nude mouse model was established with U373-R cell subcutaneous tumor-bearing mice, and results showed that SFN could remarkably suppress cell growth and enhance cell death in chemo-resistant xenografts in the nude mouse model. Collectively, the present study suggests that the clinical efficacy of TMZ-based chemotherapy in TMZ-resistant GBM may be improved by combination with SFN.

语种: 英语
所属项目编号: 81201973 ; 81502654 ; 81172596 ; 81482814
项目资助者: China National Natural Scientific Fund ; Beijing Health System High Level Health Technology Personnel Training Project Foundation
WOS记录号: WOS:000366897500013
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/61923
Appears in Collections:北京大学临床肿瘤学院_医学影像科_期刊论文

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作者单位: 1.Tianjin Hosp, Dept Radiat Oncol, Tianjin, Peoples R China
2.Tianjin Hosp, Dept Orthoped, Tianjin, Peoples R China
3.Fifth Cent Hosp Tianjin, Dept Gastroenterol, Tianjin, Peoples R China
4.Tianjin Huanhu Hosp, Tianjin Neurosurg Inst, Tianjin 300060, Peoples R China
5.Peking Univ, Canc Hosp, Dept Radiotherapy, Key Lab Carcinogenesis & Translat Res, Beijing 100871, Peoples R China

Recommended Citation:
Lan, Fengming,Yang, Yang,Han, Jing,et al. Sulforaphane reverses chemo-resistance to temozolomide in glioblastoma cells by NF-kappa B-dependent pathway downregulating MGMT expression[J]. INTERNATIONAL JOURNAL OF ONCOLOGY,2016,48(2):559-568.
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