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GZD824 suppresses the growth of human B cell precursor acute lymphoblastic leukemia cells by inhibiting the SRC kinase and PI3K/AKT pathways
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5675611/ https://www.ncbi.nlm.nih.gov/pubmed/29152059 http://dx.doi.org/10.18632/oncotarget.10881 |
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author | 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 |
author_facet | 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 |
author_sort | Ye, Wei |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5675611 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-56756112017-11-18 GZD824 suppresses the growth of human B cell precursor acute lymphoblastic leukemia cells by inhibiting the SRC kinase and PI3K/AKT pathways 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 Oncotarget Research Paper 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. Impact Journals LLC 2016-07-28 /pmc/articles/PMC5675611/ /pubmed/29152059 http://dx.doi.org/10.18632/oncotarget.10881 Text en Copyright: © 2017 Ye et al. http://creativecommons.org/licenses/by/3.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Research Paper 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 GZD824 suppresses the growth of human B cell precursor acute lymphoblastic leukemia cells by inhibiting the SRC kinase and PI3K/AKT pathways |
title | GZD824 suppresses the growth of human B cell precursor acute lymphoblastic leukemia cells by inhibiting the SRC kinase and PI3K/AKT pathways |
title_full | GZD824 suppresses the growth of human B cell precursor acute lymphoblastic leukemia cells by inhibiting the SRC kinase and PI3K/AKT pathways |
title_fullStr | GZD824 suppresses the growth of human B cell precursor acute lymphoblastic leukemia cells by inhibiting the SRC kinase and PI3K/AKT pathways |
title_full_unstemmed | GZD824 suppresses the growth of human B cell precursor acute lymphoblastic leukemia cells by inhibiting the SRC kinase and PI3K/AKT pathways |
title_short | GZD824 suppresses the growth of human B cell precursor acute lymphoblastic leukemia cells by inhibiting the SRC kinase and PI3K/AKT pathways |
title_sort | gzd824 suppresses the growth of human b cell precursor acute lymphoblastic leukemia cells by inhibiting the src kinase and pi3k/akt pathways |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5675611/ https://www.ncbi.nlm.nih.gov/pubmed/29152059 http://dx.doi.org/10.18632/oncotarget.10881 |
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