Rigosertib induces cell death of a myelodysplastic syndrome-derived cell line by DNA damage-induced G2/M arrest.
Rigosertib induces cell death of a myelodysplastic syndrome-derived cell line by DNA damage-induced G2/M arrest.
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DOI：
10.1111/cas.12605
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发表时间：
2015-03
期刊：
影响因子：
5.7
通讯作者：
Tohyama K
中科院分区：
文献类型：
--
作者：
Hyoda T;Tsujioka T;Nakahara T;Suemori S;Okamoto S;Kataoka M;Tohyama K
rigosertib（ON 01910.Na）是一种多激酶抑制剂，近年来被认为是治疗骨髓增生异常综合征（MDS）的新型抗癌药物，但其作用机制尚不清楚。我们研究了rigosertib对MDS衍生细胞系MDS-L和髓性白血病细胞系HL-60的体外作用。Rigosertib抑制HL-60和MDS-L细胞的增殖，并通过抑制PI 3激酶/Akt通路诱导细胞凋亡。由于对细胞周期的影响，rigosertib处理促进了组蛋白H2 AX的磷酸化，导致DNA损伤诱导的G2/M期阻滞。此外，一项免疫荧光染色研究证实了极光A激酶的异常定位，表明rigosertib导致纺锤体组装紊乱，有丝分裂模式失调，导致细胞周期停滞和细胞凋亡。我们还发现rigosertib对两种淋巴细胞系Jurkat和拉莫斯具有生长抑制作用。我们根据MDS-L细胞的基因表达谱数据进一步检查了rigosertib影响的分子途径，发现rigosertib处理可能参与微管动力学相关基因的上调和mRNA降解系统的下调。基因集富集分析表明，抑制“无义介导的mRNA衰减（NMD）”作为最显着影响的基因集。这些数据为rigosertib治疗难治性造血系统恶性肿瘤提供了一个新的方面和潜在的效用。
A multi-kinase inhibitor, rigosertib (ON 01910.Na) has recently been highlighted as a novel type of anti-cancer agent for the treatment of the myelodysplastic syndromes (MDS), but its action mechanisms remain to be clarified. We investigated the in vitro effects of rigosertib on an MDS-derived cell line MDS-L and a myeloid leukemia cell line HL-60. Rigosertib suppressed the proliferation of both HL-60 and MDS-L cells and induced apoptosis by inhibition of the PI3 kinase/Akt pathway. As the effects on cell cycle, rigosertib treatment promoted the phosphorylation of histone H2AX and led to the DNA damage-induced G2/M arrest. In addition, an immunofluorescence staining study demonstrated the abnormal localization of aurora A kinase, suggesting that rigosertib causes perturbation of spindle assembly and deregulated mitotic patterns towards cell cycle arrest and apoptosis. We also found that rigosertib exerted growth inhibitory effects on two lymphoid cell lines, Jurkat and Ramos. We further examined the molecular pathways influenced by rigosertib from the gene expression profiling data of MDS-L cells and found a possible involvement of rigosertib treatment in the upregulation of the genes related to microtubule kinetics and the downregulation of the mRNA degradation system. The gene set enrichment analysis showed the suppression of “nonsense-mediated mRNA decay (NMD)” as the most significantly affected gene set. These data provide a new aspect and a potential utility of rigosertib for the treatment of refractory hematopoietic malignancies.
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DOI：
10.1158/1541-7786.mcr-09-0502
发表时间：
2010-03
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Gardner LB
通讯作者：
Gardner LB
影响因子：
6.5
作者：
Farag SS
通讯作者：
Farag SS
影响因子：
20.3
作者：
Shi, Yuhong;Tohyama, Yumi;Yamamura, Hirohei
通讯作者：
Yamamura, Hirohei
DOI：
10.1158/1078-0432.ccr-11-2113
发表时间：
2012-04-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Chapman CM;Sun X;Roschewski M;Aue G;Farooqui M;Stennett L;Gibellini F;Arthur D;Pérez-Galán P;Wiestner A
通讯作者：
Wiestner A
影响因子：
50.3
作者：
Gumireddy, K;Reddy, MVR;Reddy, EP
通讯作者：
Reddy, EP