替莫唑胺
胶质瘤
孤雌内酯
癌症研究
基因敲除
活力测定
细胞凋亡
生物
达卡巴嗪
NF-κB
黑色素瘤
生物化学
作者
Zhiyun Yu,Yong Chen,Shiqiang Wang,Pengliang Li,Guangtong Zhou,Yongjie Yuan
标识
DOI:10.1016/j.canlet.2018.04.033
摘要
The introduction of temozolomide (TMZ) has improved chemotherapy for malignant gliomas. However, many gliomas are refractory to TMZ, so there is a pressing need for more effective therapeutic options. Here we demonstrated that glioma specimens and cell lines have constitutively high levels of nuclear factor κB (NF-κB) activity. Notably, the expression levels of this transcription factor correlated with malignant grades in glioblastoma multiforme (GBM) and inversely correlated with overall survival. Conversely, knockdown of NF-κB inhibits glioma cell proliferation and treating a panel of established glioma cell lines with pharmacological NF-κB inhibitors markedly decreased glioma viability, led to S cell cycle arrest, and induced apoptosis. We also found a significant correlation between NF-κB expression and O6-methylguanine-DNA methyltransferase (MGMT) expression in gliomas with different origins, and immunohistochemistry confirmed these findings. Genetic or pharmacological (especially parthenolide) inhibition of NF-κB activity down-regulated MGMT gene expression and substantially restored TMZ chemosensitivity in vitro and in vivo. Importantly, the TMZ sensitizing effect of siNF-κB(p65) or parthenolide were rescued by MGMT cDNA expression. These findings suggest that NF-κB is a potential target for inducing cell death in gliomas. A targeted combination strategy in which the response to TMZ is synergistically enhanced by the addition of parthenolide which may be useful, especially in chemoresistant gliomas with high MGMT expression.
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