组蛋白去乙酰化酶和蛋白酶体抑制联合作用对胰腺和肝癌细胞系的影响。
Synergistic activity of histone deacetylase and proteasome inhibition against pancreatic and hepatocellular cancer cell lines.
机构信息
Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada.
出版信息
Anticancer Res. 2011 Apr;31(4):1093-103.
AIM
To determine the phenotypic effects of belinostat (bel) and bortezomib (bor) against pancreatic cancer (PC) and hepatocellular cancer (HCC) cell lines.
MATERIALS AND METHODS
Antiproliferative effects were assessed using a sulforhodamine B assay. Synergy was evaluated using the Chou and Talalay method. Apoptosis was measured by caspase-3/-7 activity and PARP cleavage. Downstream effector proteins were detected via immunoblotting. Quantitative nuclear magnetic resonance (NMR)-based metabolomics analysis was performed.
RESULTS
There were single-agent antiproliferative effects against PC and HCC cell lines; the combination of bel and bor (bel+bor) had a synergistic effect. There was up to a 45-fold induction of apoptosis over the control. Post-treatment cell death was associated with p21 up-regulation, more pronounced with treatment with bel+bor. Treatment with bel+bor enhanced hyperacetylation of histone H3 over single-agent bel. A metabolic signature was established for treatments with bor and bel+bor.
CONCLUSION
The combination of bel+bor displayed significant antiproliferative activity against PC and HCC cell lines, with exhibiting synergistic antiproliferative and proapoptotic patterns even at suboptimal single-agent doses.
目的
确定贝林司他（bel）和硼替佐米（bor）对胰腺癌（PC）和肝细胞癌（HCC）细胞系的表型效应。
材料和方法
采用磺酰罗丹明 B 法评估抗增殖作用。采用 Chou 和 Talalay 法评估协同作用。通过 caspase-3/-7 活性和 PARP 裂解来测量细胞凋亡。通过免疫印迹检测下游效应蛋白。采用基于定量核磁共振（NMR）的代谢组学分析。
结果
对 PC 和 HCC 细胞系具有单药抗增殖作用；贝林司他和硼替佐米（bel+bor）联合具有协同作用。凋亡诱导率比对照高 45 倍。治疗后细胞死亡与 p21 上调有关，bel+bor 治疗时更为明显。贝林司他+硼替佐米治疗可增强组蛋白 H3 的超乙酰化，而单药贝林司他则没有。建立了硼替佐米和贝林司他+硼替佐米治疗的代谢特征。
结论
贝林司他+硼替佐米联合应用对 PC 和 HCC 细胞系具有显著的抗增殖活性，即使在亚最佳单药剂量下，也表现出协同的抗增殖和促凋亡作用。
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