Targeting the wee1 kinase for treatment of pediatric Down syndrome acute myeloid leukemia.
Targeting the wee1 kinase for treatment of pediatric Down syndrome acute myeloid leukemia.
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DOI：
10.1002/pbc.25081
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发表时间：
2014-10
影响因子：
3.2
通讯作者：
Taub, Jeffrey W.
中科院分区：
文献类型：
--
作者：
Caldwell, J. Timothy;Edwards, Holly;Buck, Steven A.;Ge, Yubin;Taub, Jeffrey W.
大多数患有急性髓细胞白血病（DS-AML）的唐氏综合征儿童具有总体良好的预后，然而，遭受诱导失败或复发的患者具有极差的预后。因此，需要为该DS-AML患者亚组开发新的治疗方法。一种新的治疗方法是通过用一流的抑制剂MK-1775与标准遗传毒性剂阿糖胞苷（AraC）组合抑制上游激酶wee 1来防止细胞周期检查点激活。使用临床相关DS-AML细胞系CMK和CMY以及离体原发性DS-AML患者样本，采用MTT试验研究了MK-1775增强AraC细胞毒性的能力。在细胞系中研究了MK-1775增强AraC细胞毒性的机制，使用蛋白质印迹法探测CDK 1和H2 AX磷酸化，并使用流式细胞术测定细胞凋亡、细胞周期阻滞、DNA损伤和异常有丝分裂进入。MK-1775单独具有适度的单药活性，然而，MK-1775能够与AraC协同作用，在细胞系和原发性患者样品中引起增殖停滞，并增强AraC诱导的细胞凋亡。MK-1775在100 nM的相对低浓度下仅在4小时后就能够降低抑制性CDK 1（Y15）磷酸化。此外，它能够增强AraC诱导的DNA损伤，并部分消除细胞周期阻滞。重要的是，DNA损伤增强出现在早期S期。MK-1775能够增强AraC在DS-AML细胞中的细胞毒性，并为DS-AML提供了一种有前途的新治疗方法。
Most Down syndrome children with acute myeloid leukemia (DS-AML) have an overall excellent prognosis, however, patients who suffer an induction failure or relapse, have an extremely poor prognosis. Hence, new therapies need to be developed for this subgroup of DS-AML patients. One new therapeutic approach is preventing cell cycle checkpoint activation by inhibiting the upstream kinase wee1 with the first-in-class inhibitor MK-1775 in combination with the standard genotoxic agent cytarabine (AraC). Using the clinically relevant DS-AML cell lines CMK and CMY, as well as ex vivo primary DS-AML patient samples, the ability of MK-1775 to enhance the cytotoxicity of AraC was investigated with MTT assays. The mechanism by which MK-1775 enhanced AraC cytotoxicity was investigated in the cell lines using Western blots to probe CDK1 and H2AX phosphorylation and flow cytometry to determine apoptosis, cell cycle arrest, DNA damage, and aberrant mitotic entry. MK-1775 alone had modest single-agent activity, however, MK-1775 was able to synergize with AraC in causing proliferation arrest in both cell lines and primary patient samples, and enhance AraC-induced apoptosis. MK-1775 was able to decrease inhibitory CDK1(Y15) phosphorylation at the relatively low concentration of 100 nM after only 4 hours. Furthermore, it was able to enhance DNA damage induced by AraC and partially abrogate cell cycle arrest. Importantly, the DNA damage enhancement appeared in early S-phase. MK-1775 is able to enhance the cytotoxicity of AraC in DS-AML cells and presents a promising new treatment approach for DS-AML.
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DOI：
10.1083/jcb.200905059
发表时间：
2010-03-08
期刊：
The Journal of cell biology
影响因子：
--
作者：
Beck H;Nähse V;Larsen MS;Groth P;Clancy T;Lees M;Jørgensen M;Helleday T;Syljuåsen RG;Sørensen CS
通讯作者：
Sørensen CS
影响因子：
10.3
作者：
Ge, YB;Stout, ML;Taub, JW
通讯作者：
Taub, JW
影响因子：
28.2
作者：
Aarts, Marieke;Sharpe, Rachel;Turner, Nicholas C.
通讯作者：
Turner, Nicholas C.
影响因子：
4.3
作者：
Hitzler, Johann K.;He, Wensheng;Carpenter, Paul A.
通讯作者：
Carpenter, Paul A.
影响因子：
11.2
作者：
Ge, YB;Jensen, TL;Taub, JW
通讯作者：
Taub, JW