HDAC inhibition synergistically enhances alkylator-induced DNA damage responses and apoptosis in multiple myeloma cells.
HDAC inhibition synergistically enhances alkylator-induced DNA damage responses and apoptosis in multiple myeloma cells.
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DOI：
10.1016/j.canlet.2010.04.014
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发表时间：
2010-10-28
期刊：
影响因子：
9.7
通讯作者：
Liu, Bolin
中科院分区：
文献类型：
--
作者：
Lee, Choon-Kee;Wang, Shuiliang;Huang, Xiaoping;Ryder, John;Liu, Bolin
组蛋白去乙酰化酶（HDAC）抑制剂诱导染色质去稳定化。我们试图确定HDAC抑制是否可以放大烷化剂诱导的多发性骨髓瘤（MM）细胞有丝分裂细胞死亡。SNDX-275（一种I类HDAC抑制剂）与美法仑的组合在MM1.S和RPMI 8226细胞中显示出对生长抑制的强大协同作用，组合指数范围为0.27至0.75。它们的组合相比，任何一种药物单独促进更多的半胱天冬酶依赖性细胞凋亡。流式细胞仪分析表明，SNDX-275对MM 1.S细胞周期进程的影响很小，但明显增加了RPMI 8226细胞中S期的百分比，并与p21 waf 1的上调和cyclin D1和E2 F1的减少相关。美法仑单独使用可显著阻滞MM1.S和RPMI 8226细胞于S期，并增强p53和p21 waf 1的表达。此外，DNA损伤反应的研究表明，SNDX-275或美法仑可显著诱导磷酸化组蛋白H2A.X（γH2A.X），沿着磷酸化CHK 1（P-CHK 1）和CHK 2（P-CHK 2）。γH2A.X和P-CHK 1的增加在组合时显著高于任一药剂单独使用。这些分子变化与有丝分裂灾难的显著增加密切相关。我们的数据表明，SNDX-275协同增强美法仑诱导的MM细胞凋亡，通过加强DNA损伤，这表明SNDX-275与美法仑组合可能是一种新的治疗MM的策略。
Histone deacetylase (HDAC) inhibitors induce chromatin destabilization. We sought to determine whether HDAC inhibition may amplify alkylator-induced mitotic cell death in multiple myeloma (MM) cells. The combination of SNDX-275, a class I HDAC inhibitor, with melphalan, showed a powerful synergism on growth inhibition with the combination index ranged from 0.27 to 0.75 in MM1.S and RPMI8226 cells. Their combinations as compared with either agent alone promoted much more caspase-dependent apoptosis. Flow cytometry analysis showed that SNDX-275 had minimal effects on cell cycle progression of MM1.S cells, but clearly increased the percentage of S phase in RPMI8226 cells associated with an upregulation in p21waf1 and a reduction in cyclin D1 and E2F1. Melphalan alone significantly arrested both MM1.S and RPMI8226 cells at S phase and enhanced expression of p53 and p21waf1. Furthermore, studies on DNA damage response revealed that phospho-histone H2A.X (γH2A.X), a hall marker of DNA double strand break, along with phosphorylated CHK1 (P-CHK1) and CHK2 (P-CHK2) was dramatically induced by SNDX-275 or melphalan. The increase in γH2A.X and P-CHK1 was considerably higher on combination than either agent alone. These molecular changes correlated well with the significant increase in mitotic catastrophe. Our data indicate that SNDX-275 synergistically enhances melphalan-induced apoptosis in MM cells via intensification of DNA damage, suggesting that SNDX-275 in combination with melphalan may be a novel therapeutic strategy for MM.
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影响因子：
20.3
作者：
Catley, Laurence;Weisberg, Ellen;Anderson, Kenneth C.
通讯作者：
Anderson, Kenneth C.
影响因子：
11.4
作者：
Lucas, DM;Davis, ME;Grever, MR
通讯作者：
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DOI：
10.1158/1078-0432.ccr-08-2444
发表时间：
2009-03-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Labrinidis A;Diamond P;Martin S;Hay S;Liapis V;Zinonos I;Sims NA;Atkins GJ;Vincent C;Ponomarev V;Findlay DM;Zannettino AC;Evdokiou A
通讯作者：
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影响因子：
11.2
作者：
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影响因子：
20.3
作者：
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