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本文引用的文献

1
Effects of selective checkpoint kinase 1 inhibition on cytarabine cytotoxicity in acute myelogenous leukemia cells in vitro.选择性细胞周期检查点激酶 1 抑制对体外急性髓系白血病细胞中阿糖胞苷细胞毒性的影响。
Clin Cancer Res. 2012 Oct 1;18(19):5364-73. doi: 10.1158/1078-0432.CCR-12-0961. Epub 2012 Aug 6.
2
Sensitization of pancreatic cancer stem cells to gemcitabine by Chk1 inhibition.抑制 Chk1 可使胰腺癌干细胞对吉西他滨敏感。
Neoplasia. 2012 Jun;14(6):519-25. doi: 10.1593/neo.12538.
3
Human embryonic stem cells fail to activate CHK1 and commit to apoptosis in response to DNA replication stress.人类胚胎干细胞在应对 DNA 复制压力时无法激活 CHK1 并促使其凋亡。
Stem Cells. 2012 Jul;30(7):1385-93. doi: 10.1002/stem.1117.
4
Targeting Chk1 in p53-deficient triple-negative breast cancer is therapeutically beneficial in human-in-mouse tumor models.针对 p53 缺陷型三阴性乳腺癌中的 Chk1 进行靶向治疗在人源化小鼠肿瘤模型中具有治疗益处。
J Clin Invest. 2012 Apr;122(4):1541-52. doi: 10.1172/JCI58765. Epub 2012 Mar 26.
5
Evaluation of checkpoint kinase targeting therapy in acute myeloid leukemia with complex karyotype.评价有复杂核型的急性髓系白血病的检查点激酶靶向治疗。
Cancer Biol Ther. 2012 Mar;13(5):307-13. doi: 10.4161/cbt.19074. Epub 2012 Mar 1.
6
Preclinical development of the novel Chk1 inhibitor SCH900776 in combination with DNA-damaging agents and antimetabolites.新型 Chk1 抑制剂 SCH900776 与 DNA 损伤药物和抗代谢物联合的临床前开发。
Mol Cancer Ther. 2012 Feb;11(2):427-38. doi: 10.1158/1535-7163.MCT-11-0406. Epub 2011 Dec 27.
7
HDAC inhibitors in cancer biology: emerging mechanisms and clinical applications.组蛋白去乙酰化酶抑制剂在癌症生物学中的作用:新兴机制和临床应用。
Immunol Cell Biol. 2012 Jan;90(1):85-94. doi: 10.1038/icb.2011.100. Epub 2011 Nov 29.
8
Therapeutic targeting of Chk1 in NSCLC stem cells during chemotherapy.在化疗期间针对 NSCLC 干细胞中的 Chk1 进行治疗性靶向治疗。
Cell Death Differ. 2012 May;19(5):768-78. doi: 10.1038/cdd.2011.170. Epub 2011 Nov 25.
9
Role of checkpoint kinase 1 (Chk1) in the mechanisms of resistance to histone deacetylase inhibitors.检查点激酶 1(Chk1)在组蛋白去乙酰化酶抑制剂耐药机制中的作用。
Proc Natl Acad Sci U S A. 2011 Dec 6;108(49):19629-34. doi: 10.1073/pnas.1117544108. Epub 2011 Nov 21.
10
Safeguarding genome integrity: the checkpoint kinases ATR, CHK1 and WEE1 restrain CDK activity during normal DNA replication.保障基因组完整性:检查点激酶 ATR、CHK1 和 WEE1 在正常 DNA 复制过程中抑制 CDK 活性。
Nucleic Acids Res. 2012 Jan;40(2):477-86. doi: 10.1093/nar/gkr697. Epub 2011 Sep 21.

新型 Chk1 抑制剂 MK-8776 通过靶向细胞内 S 检查点及 DNA 复制和修复,增强人白血病细胞对 HDAC 抑制剂的敏感性。

The novel Chk1 inhibitor MK-8776 sensitizes human leukemia cells to HDAC inhibitors by targeting the intra-S checkpoint and DNA replication and repair.

机构信息

Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA.

出版信息

Mol Cancer Ther. 2013 Jun;12(6):878-89. doi: 10.1158/1535-7163.MCT-12-0902. Epub 2013 Mar 27.

DOI:10.1158/1535-7163.MCT-12-0902
PMID:23536721
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3681875/
Abstract

Interactions between the novel Chk1 inhibitor MK-8776 and the histone deacetylase (HDAC) inhibitor (HDACI) vorinostat were examined in human leukemia cells harboring wild-type (wt) or deficient p53. MK-8776 synergistically potentiated vorinostat-mediated apoptosis in various p53-wt or -deficient leukemia cell lines, whereas p53 knockdown by short hairpin RNA (shRNA) sensitized p53-wt cells to lethality of this regimen. Leukemia cell lines carrying FLT3-ITD were also sensitive to the MK-8776/vorinostat regimen. Synergistic interactions were associated with inhibition of Chk1 activity, interference with the intra-S-phase checkpoint, disruption of DNA replication, and downregulation of proteins involved in DNA replication (e.g., Cdt1) and repair (e.g., CtIP and BRCA1), resulting in sharp increases in DNA damage, reflected by enhanced γ-H2A.X formation, and apoptosis. Moreover, leukemia cells expressing kinase-dead Chk1 (D130A) or Chk1 shRNA were significantly more sensitive to HDACIs compared with their wt counterparts and displayed downregulation of CtIP and BRCA1 phosphorylation following HDACI exposure. Finally, the MK-8776/vorinostat regimen was active in primary acute myelogenous leukemia (AML) blasts, particularly against the CD34(+)/CD38(-)/CD123(+) population enriched for leukemia-initiating cells. In contrast, identical regimens were relatively sparing toward normal cord blood CD34(+) cells. Together, these findings indicate that the novel Chk1 inhibitor MK-8776 markedly potentiates HDACI lethality in leukemia cells displaying various genetic backgrounds through mechanisms involving disruption of the intra-S checkpoint, DNA replication, and DNA repair. They also argue that leukemic cells, including those bearing oncogenic mutations associated with poor prognosis, for example, p53 deletion/mutation or FLT3-ITD, may also be susceptible to this strategy.

摘要

新型 Chk1 抑制剂 MK-8776 与组蛋白去乙酰化酶(HDAC)抑制剂(HDACI)伏立诺他之间的相互作用在携带野生型(wt)或缺陷型 p53 的人白血病细胞中进行了研究。MK-8776 与各种 p53-wt 或 -deficient 白血病细胞系中的伏立诺他介导的细胞凋亡协同增强,而短发夹 RNA(shRNA)对 p53 的敲低使 p53-wt 细胞对该方案的致死性敏感。携带 FLT3-ITD 的白血病细胞系也对 MK-8776/伏立诺他方案敏感。协同作用与 Chk1 活性的抑制、干扰 S 期内检查点、破坏 DNA 复制以及下调参与 DNA 复制(例如 Cdt1)和修复(例如 CtIP 和 BRCA1)的蛋白质有关,导致 DNA 损伤急剧增加,表现为γ-H2A.X 形成和细胞凋亡增强。此外,表达激酶失活的 Chk1(D130A)或 Chk1 shRNA 的白血病细胞对 HDACIs 的敏感性明显高于其 wt 对应物,并且在暴露于 HDACI 后表现出 CtIP 和 BRCA1 磷酸化的下调。最后,MK-8776/伏立诺他方案对原发性急性髓性白血病(AML)blasts 有效,特别是针对富含白血病起始细胞的 CD34(+)/CD38(-)/CD123(+)群体。相比之下,相同的方案对正常脐带血 CD34(+)细胞相对较少。总之,这些发现表明,新型 Chk1 抑制剂 MK-8776 通过破坏 S 期内检查点、DNA 复制和 DNA 修复等机制,显著增强了具有各种遗传背景的白血病细胞中 HDACI 的致死性。它们还表明,包括携带与预后不良相关的致癌突变的白血病细胞(例如 p53 缺失/突变或 FLT3-ITD)在内的白血病细胞也可能对这种策略敏感。