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题目:: GZD824 suppresses the growth of human B cell precursor acute lymphoblastic leukemia cells by inhibiting the SRC kinase and PI3K/AKT pathways.
作者:: Ye(Wei),Jiang(Zhiwu),Lu(Xiaoyun),Ren(Xiaomei),Deng(Manman),Lin(Shouheng),Xiao(Yiren),Lin(Simiao),Wang(Suna),Li(Baiheng),Zheng(Yi),Lai(Peilong),Weng(Jianyu),Wu(Donghai),Ma(Yuguo),Chen(Xudong),Wen(Zhesheng),Chen(Yaoyu),Feng(Xiaoyan),Li(Yangqiu),Liu(Pentao),Du(Xin),Pei(Duanqing),Yao(Yao),Xu(Bing),Ding(Ke),Li(Peng)
状态:: 发布时间2016-08-03 , 更新时间 2016-08-03
期刊:: Oncotarget
摘要:: Available therapeutic options for advanced B cell precursor acute lymphoblastic leukemia (pre-B ALL) are limited. Many lead to neutropenia, leaving patients at risk of life-threatening infections and result in bad outcomes. New treatment options are needed to improve overall survival. We previously showed that GZD824, a novel BCR-ABL tyrosine kinase inhibitor, has anti-tumor activity in Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia cells and tumor models. Here, we show that GZD824 decreases cell viability, induces cell-cycle arrest, and causes apoptosis in pre-B ALL cells. Furthermore, Ph- pre-B ALL cells were more sensitive to GZD824 than Ph+ pre-B ALL cells. GZD824 consistently reduced tumor loads in Ph- pre-B ALL xenografts but failed to suppress Ph+ pre-B ALL xenografts. GZD824 decreased phosphorylation of SRC kinase, STAT3, RB and C-myc. It also downregulated the expression of BCL-XL, CCND1 and CDK4 and upregulated expression of CCKN1A. Expression of IRS1 was decreased in GZD824-treated pre-B ALL cells, blocking the PI3K/AKT pathway. These data demonstrate that GZD824 suppresses pre-B ALL cells through inhibition of the SRC kinase and PI3K/AKT pathways and may be a potential therapeutic agent for the management of pre-B ALL.
语言:: eng
DOI:: 10.18632/oncotarget.10881

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