Enhanced efficacy of histone deacetylase inhibitor combined with bromodomain inhibitor in glioblastoma.
Enhanced efficacy of histone deacetylase inhibitor combined with bromodomain inhibitor in glioblastoma.
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组蛋白脱乙酰酶抑制剂联合溴结构域抑制剂增强胶质母细胞瘤疗效
DOI：
10.1186/s13046-018-0916-y
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发表时间：
2018-10-01
期刊：
影响因子：
--
通讯作者：
Ma J
中科院分区：
文献类型：
--
作者：
Meng W;Wang B;Mao W;Wang J;Zhao Y;Li Q;Zhang C;Tang Y;Ma J
背景胶质母细胞瘤（GBM）是成人最常见、恶性程度最高的原发性脑肿瘤。尽管采用多种治疗方法，但预后仍然很差。因此，迫切需要进一步的工作，以发现新的治疗策略GBM treatment.MethodsThe协同作用的协同治疗与组蛋白去乙酰化酶（HDAC）抑制剂帕比司他和布罗莫结构域抑制剂JQ 1或OTX 015进行了验证，在GBM细胞系的细胞活力测定。此外，通过EdU增殖测定，凋亡测定，qPCR，蛋白质印迹和RNAseq analysis.ResultsWe发现，与帕比司他和JQ 1或OTX 015协同抑制GBM细胞中的细胞活力的共处理的抑制机制进行了研究。帕比司他和JQ 1或OTX 015的共处理显著抑制GBM细胞的细胞增殖并诱导细胞凋亡。与单独使用每种药物的治疗相比，帕比司他和JQ 1的共同治疗诱导了更深刻的caspase 3/7活化和细胞毒性。机制研究表明，Panobinostat与JQ 1或OTX 015联用，对GBM相关致癌基因或通路的抑制作用更强，对GBM相关抑瘤基因的诱导作用更强。HDAC抑制剂和布罗莫结构域抑制剂的联合治疗在GBM治疗中值得进一步关注。
BackgroundGlioblastoma (GBM) is the most common and most malignant primary brain cancer in adults. Despite multimodality treatment, the prognosis is still poor. Therefore, further work is urgently required to discover novel therapeutic strategies for GBM treatment.MethodsThe synergistic effects of cotreatment with the histone deacetylase (HDAC) inhibitor panobinostat and bromodomain inhibitor JQ1 or OTX015 were validated using cell viability assays in GBM cell lines. Furthermore, the inhibitory mechanisms were investigated via an EdU proliferation assay, an apoptosis assay, qPCR, Western blot and RNAseq analyses.ResultsWe found that the cotreatment with panobinostat and JQ1 or OTX015 synergistically inhibited cell viability in GBM cells. The cotreatment with panobinostat and JQ1 or OTX015 markedly inhibited cell proliferation and induced apoptosis in GBM cells. Compared with treatment with each drug alone, the cotreatment with panobinostat and JQ1 induced more profound caspase 3/7 activation and cytotoxicity. Mechanistic investigation showed that combination of panobinostat with JQ1 or OTX015 results in stronger repression of GBM-associated oncogenic genes or pathways as well as higher induction of GBM-associated tumor-suppressive genes.ConclusionOur study demonstrated that HDAC inhibitor and bromodomain inhibitor had synergistical efficacy against GBM cells. The cotreatment with HDAC inhibitor and bromodomain inhibitor warrants further attention in GBM therapy.
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影响因子：
3.9
作者：
Music, Darija;Dahlrot, Rikke Hedegaard;Kristensen, Bjarne Winther
通讯作者：
Kristensen, Bjarne Winther
DOI：
10.1158/1078-0432.ccr-12-3066
发表时间：
2013-04-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Cheng Z;Gong Y;Ma Y;Lu K;Lu X;Pierce LA;Thompson RC;Muller S;Knapp S;Wang J
通讯作者：
Wang J
影响因子：
4.7
作者：
Jiang, ZH;Zheng, X;Rich, KM
通讯作者：
Rich, KM
影响因子：
3.7
作者：
Pastori C;Daniel M;Penas C;Volmar CH;Johnstone AL;Brothers SP;Graham RM;Allen B;Sarkaria JN;Komotar RJ;Wahlestedt C;Ayad NG
通讯作者：
Ayad NG
影响因子：
--
作者：
Cui D;Sajan P;Shi J;Shen Y;Wang K;Deng X;Zhou L;Hu P;Gao L
通讯作者：
Gao L