Antitumor action of CDK inhibitor LS-007 as a single agent and in combination with ABT-199 against human acute leukemia cells

doi:10.1038/aps.2016.49

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第一研究室

	Antitumor action of CDK inhibitor LS-007 as a single agent and in combination with ABT-199 against human acute leukemia cells
	Xie, Shao 1; Jiang, Hui 2; Zhai, Xiao-wen 3; Wei, Fan 1; Wang, Shu-dong 4; Ding, Jian1 ; Chen, Yi1
刊名	ACTA PHARMACOLOGICA SINICA
	2016-11
卷号	37 期号:11 页码:1481-1489
关键词	acute leukemia CDK9 LS-007 ABT-199 apoptosis drug synergism
ISSN号	1671-4083
DOI	10.1038/aps.2016.49
文献子类	Article
英文摘要	Aim: LS-007 is a CDK inhibitor, which exhibits potent antitumor activity against chronic lymphocytic leukemia and ovarian cancer cells. In this study, we further evaluated the antitumor activity of LS-007 alone and in combination with a Bcl-2 inhibitor ABT-199 in acute leukemia (AL) cells. Methods: Cell viability was detected using resazurin assay, and cell apoptosis was examined using Annexin V/PI double staining and flow cytometry. The inhibition of LS-007 on kinases was evaluated with the mobility shift assay or ELISA. The expression of relevant signaling molecules was assessed using Western blotting and RT-PCR. Primary lymphocytes from patients with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) were separated using Ficoll-Paque PLUS. Results: LS-007 inhibited the proliferation of 6 AL cell lines with IC50 values of 100-200 nmol/L, and decreased the survival of ALL and AML patient-derived lymphocytes with mean LD50 value of 67 and 102 nmol/L, respectively. In kinase assays in vitro, LS-007 was more selective for the CDK family, inhibiting CDK2, CDK9, CDK1 and CDK4 at low nanomolar concentrations. In HL-60 and CCRF-CEM cells, LS-007 (0.1-0.4 mu mol/L) dose-dependently induced cell apoptosis predominantly through CDK9 inhibition-related dephosphorylation at the ser2 residue of RNA pol II and the corresponding depletion of anti-apoptotic proteins, especially Mcl-1 and XIAP. LS-007 (0.2 and 0.4 mu mol/L) also induced cell apoptosis in the patient-derived lymphocytes. In HL-60, CCRF-CEM and Molt-4 cells, combined application of LS-007 with ABT-199 (1 or 2 mu mol/L) markedly increased cell apoptosis with a maximal decrease in the XIAP levels as compared with either drug used alone. Conclusion: CDK inhibitor LS-007 potently inhibits the established human AL cell lines and primary AL blasts, and it also shows remarkable synergy with Bcl-2 inhibitor ABT-199.
资助项目	National Natural Science Foundation of China[81521005] ; National Basic Research Program of China[2013CB932503]
WOS关键词	ACUTE LYMPHOBLASTIC-LEUKEMIA ; DEPENDENT KINASE INHIBITOR ; ACUTE MYELOID-LEUKEMIA ; CHRONIC LYMPHOCYTIC-LEUKEMIA ; CANCER-CELLS ; SIGNALING PATHWAY ; DRUG TARGET ; IN-VIVO ; APOPTOSIS ; BCL-2
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
CSCD记录号	CSCD:5841415
出版者	ACTA PHARMACOLOGICA SINICA
WOS记录号	WOS:000387755900010
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/275835]
专题	药理学第一研究室中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Ding, Jian; Chen, Yi
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 2.Shanghai Jiao Tong Univ, Shanghai Childrens Hosp, Dept Hematol, Shanghai 200040, Peoples R China; 3.Fudan Univ, Dept Hematol & Oncol, Childrens Hosp, Shanghai 201102, Peoples R China; 4.Univ South Australia, Sch Pharm & Med Sci, Adelaide, SA 5001, Australia
推荐引用方式 GB/T 7714	Xie, Shao,Jiang, Hui,Zhai, Xiao-wen,et al. Antitumor action of CDK inhibitor LS-007 as a single agent and in combination with ABT-199 against human acute leukemia cells[J]. ACTA PHARMACOLOGICA SINICA,2016,37(11):1481-1489.
APA	Xie, Shao.,Jiang, Hui.,Zhai, Xiao-wen.,Wei, Fan.,Wang, Shu-dong.,...&Chen, Yi.(2016).Antitumor action of CDK inhibitor LS-007 as a single agent and in combination with ABT-199 against human acute leukemia cells.ACTA PHARMACOLOGICA SINICA,37(11),1481-1489.
MLA	Xie, Shao,et al."Antitumor action of CDK inhibitor LS-007 as a single agent and in combination with ABT-199 against human acute leukemia cells".ACTA PHARMACOLOGICA SINICA 37.11(2016):1481-1489.