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Small molecule activation of NOTCH signaling inhibits acute myeloid leukemia

Aberrant activation of the NOTCH signaling pathway is crucial for the onset and progression of T cell leukemia. Yet recent studies also suggest a tumor suppressive role of NOTCH signaling in acute myeloid leukemia (AML) and reactivation of this pathway offers an attractive opportunity for anti-AML t...

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Autores principales: Ye, Qi, Jiang, Jue, Zhan, Guanqun, Yan, Wanyao, Huang, Liang, Hu, Yufeng, Su, Hexiu, Tong, Qingyi, Yue, Ming, Li, Hua, Yao, Guangmin, Zhang, Yonghui, Liu, Hudan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4876435/
https://www.ncbi.nlm.nih.gov/pubmed/27211848
http://dx.doi.org/10.1038/srep26510
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author Ye, Qi
Jiang, Jue
Zhan, Guanqun
Yan, Wanyao
Huang, Liang
Hu, Yufeng
Su, Hexiu
Tong, Qingyi
Yue, Ming
Li, Hua
Yao, Guangmin
Zhang, Yonghui
Liu, Hudan
author_facet Ye, Qi
Jiang, Jue
Zhan, Guanqun
Yan, Wanyao
Huang, Liang
Hu, Yufeng
Su, Hexiu
Tong, Qingyi
Yue, Ming
Li, Hua
Yao, Guangmin
Zhang, Yonghui
Liu, Hudan
author_sort Ye, Qi
collection PubMed
description Aberrant activation of the NOTCH signaling pathway is crucial for the onset and progression of T cell leukemia. Yet recent studies also suggest a tumor suppressive role of NOTCH signaling in acute myeloid leukemia (AML) and reactivation of this pathway offers an attractive opportunity for anti-AML therapies. N-methylhemeanthidine chloride (NMHC) is a novel Amaryllidaceae alkaloid that we previously isolated from Zephyranthes candida, exhibiting inhibitory activities in a variety of cancer cells, particularly those from AML. Here, we report NMHC not only selectively inhibits AML cell proliferation in vitro but also hampers tumor development in a human AML xenograft model. Genome-wide gene expression profiling reveals that NMHC activates the NOTCH signaling. Combination of NMHC and recombinant human NOTCH ligand DLL4 achieves a remarkable synergistic effect on NOTCH activation. Moreover, pre-inhibition of NOTCH by overexpression of dominant negative MAML alleviates NMHC-mediated cytotoxicity in AML. Further mechanistic analysis using structure-based molecular modeling as well as biochemical assays demonstrates that NMHC docks in the hydrophobic cavity within the NOTCH1 negative regulatory region (NRR), thus promoting NOTCH1 proteolytic cleavage. Our findings thus establish NMHC as a potential NOTCH agonist that holds great promises for future development as a novel agent beneficial to patients with AML.
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spelling pubmed-48764352016-06-06 Small molecule activation of NOTCH signaling inhibits acute myeloid leukemia Ye, Qi Jiang, Jue Zhan, Guanqun Yan, Wanyao Huang, Liang Hu, Yufeng Su, Hexiu Tong, Qingyi Yue, Ming Li, Hua Yao, Guangmin Zhang, Yonghui Liu, Hudan Sci Rep Article Aberrant activation of the NOTCH signaling pathway is crucial for the onset and progression of T cell leukemia. Yet recent studies also suggest a tumor suppressive role of NOTCH signaling in acute myeloid leukemia (AML) and reactivation of this pathway offers an attractive opportunity for anti-AML therapies. N-methylhemeanthidine chloride (NMHC) is a novel Amaryllidaceae alkaloid that we previously isolated from Zephyranthes candida, exhibiting inhibitory activities in a variety of cancer cells, particularly those from AML. Here, we report NMHC not only selectively inhibits AML cell proliferation in vitro but also hampers tumor development in a human AML xenograft model. Genome-wide gene expression profiling reveals that NMHC activates the NOTCH signaling. Combination of NMHC and recombinant human NOTCH ligand DLL4 achieves a remarkable synergistic effect on NOTCH activation. Moreover, pre-inhibition of NOTCH by overexpression of dominant negative MAML alleviates NMHC-mediated cytotoxicity in AML. Further mechanistic analysis using structure-based molecular modeling as well as biochemical assays demonstrates that NMHC docks in the hydrophobic cavity within the NOTCH1 negative regulatory region (NRR), thus promoting NOTCH1 proteolytic cleavage. Our findings thus establish NMHC as a potential NOTCH agonist that holds great promises for future development as a novel agent beneficial to patients with AML. Nature Publishing Group 2016-05-23 /pmc/articles/PMC4876435/ /pubmed/27211848 http://dx.doi.org/10.1038/srep26510 Text en Copyright © 2016, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Ye, Qi
Jiang, Jue
Zhan, Guanqun
Yan, Wanyao
Huang, Liang
Hu, Yufeng
Su, Hexiu
Tong, Qingyi
Yue, Ming
Li, Hua
Yao, Guangmin
Zhang, Yonghui
Liu, Hudan
Small molecule activation of NOTCH signaling inhibits acute myeloid leukemia
title Small molecule activation of NOTCH signaling inhibits acute myeloid leukemia
title_full Small molecule activation of NOTCH signaling inhibits acute myeloid leukemia
title_fullStr Small molecule activation of NOTCH signaling inhibits acute myeloid leukemia
title_full_unstemmed Small molecule activation of NOTCH signaling inhibits acute myeloid leukemia
title_short Small molecule activation of NOTCH signaling inhibits acute myeloid leukemia
title_sort small molecule activation of notch signaling inhibits acute myeloid leukemia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4876435/
https://www.ncbi.nlm.nih.gov/pubmed/27211848
http://dx.doi.org/10.1038/srep26510
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