Simultaneous targeting of PI3K delta and a PI3K delta-dependent MEK1/2-Erk1/2 pathway for therapy in pediatric B-cell acute lymphoblastic leukemia
文献类型：期刊论文
| 作者 | Wang, Xiang2; Zhang, Xi2; Li, Ben-shang4; Zhai, Xiaowen5; Yang, Zhuo3; Ding, Li-xia4; Wang, Hongsheng5; Liang, Chris1; Zhu, Weiliang3 ; Ding, Jian2
|
| 刊名 | ONCOTARGET
 |
| 出版日期 | 2014-11-15 |
| 卷号 | 5期号:21页码:10732-10744 |
| 关键词 | PI-3Kdelta inhibitor MAPK B cell acute lymphocytic leukemia target therapy |
| ISSN号 | 1949-2553 |
| DOI | 10.18632/oncotarget.2533 |
| 文献子类 | Article |
| 英文摘要 | B cell acute lymphoblastic leukemia (B-ALL) is the most common hematological malignancy diagnosed in children, and blockade of the abnormally activated PI3K delta displayed promising outcomes in B cell acute or chronic leukemias, but the mechanisms are not well understood. Here we report a novel PI3K delta selective inhibitor X-370, which displays distinct binding mode with p110 delta and blocks constitutively active or stimulus-induced PI3K delta signaling. X-370 significantly inhibited survival of human B cell leukemia cells in vitro, with associated induction of G1 phase arrest and apoptosis. X-370 abrogated both Akt and Erk1/2 signaling via blockade of PDK1 binding to and/or phosphorylation of MEK1/2. Forced expression of a constitutively active MEK1 attenuated the antiproliferative activity of X-370. X-370 preferentially inhibited the survival of primary pediatric B-ALL cells displaying PI3K delta-dependent Erk1/2 phosphorylation, while combined inhibition of PI3K delta and MEK1/2 displayed enhanced activity. We conclude that PI3K delta inhibition led to abrogation of both Akt and Erk1/2 signaling via a novel PI3K-PDK1/MEK1/2-Erk1/2 signaling cascade, which contributed to its efficacy against B-ALL. These findings support the rationale for clinical testing of PI3K delta inhibitors in pediatric B-ALL and provide insights needed to optimize the therapeutic strategy. |
| WOS关键词 | PHOSPHATIDYLINOSITOL 3-KINASE ; BREAST-CANCER ; LUNG-CANCER ; PI3K ; INHIBITOR ; GROWTH ; RESISTANCE ; RAPAMYCIN ; CAL-101 ; MODELS |
| 资助项目 | National Science & Technology Major Project[2012ZX09301-001] ; National Natural Science Foundation of China[81321092] ; National Natural Science Foundation of China[81373445] ; National Natural Science Foundation of China[81402972] |
| WOS研究方向 | Oncology ; Cell Biology |
| 语种 | 英语 |
| WOS记录号 | WOS:000348036900040 |
| 出版者 | IMPACT JOURNALS LLC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/276833]  |
| 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 | Meng, Ling-hua |
| 作者单位 | 1.Xcovery LLC, W Palm Beach, FL USA 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, Shanghai 200031, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Drug Discovery & Design Ctr, Shanghai 200031, Peoples R China; 4.Shanghai Jiao Tong Univ, Dept Hematol & Oncol, Sch Med, Shanghai 200030, Peoples R China; 5.Fudan Univ, Dept Hematol & Oncol, Childrens Hosp, Shanghai 200433, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Wang, Xiang,Zhang, Xi,Li, Ben-shang,et al. Simultaneous targeting of PI3K delta and a PI3K delta-dependent MEK1/2-Erk1/2 pathway for therapy in pediatric B-cell acute lymphoblastic leukemia[J]. ONCOTARGET,2014,5(21):10732-10744. |
| APA | Wang, Xiang.,Zhang, Xi.,Li, Ben-shang.,Zhai, Xiaowen.,Yang, Zhuo.,...&Meng, Ling-hua.(2014).Simultaneous targeting of PI3K delta and a PI3K delta-dependent MEK1/2-Erk1/2 pathway for therapy in pediatric B-cell acute lymphoblastic leukemia.ONCOTARGET,5(21),10732-10744. |
| MLA | Wang, Xiang,et al."Simultaneous targeting of PI3K delta and a PI3K delta-dependent MEK1/2-Erk1/2 pathway for therapy in pediatric B-cell acute lymphoblastic leukemia".ONCOTARGET 5.21(2014):10732-10744. |
入库方式： OAI收割
来源：上海药物研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。