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ACC010, a novel BRD4 inhibitor, synergized with homoharringtonine in acute myeloid leukemia with FLT3 ‐ITD
Bromodomain‐containing protein 4 (BRD4) inhibitors have been clinically developed to treat acute myeloid leukemia (AML), but their application is limited by the possibility of drug resistance, which is reportedly associated with the activation of the WNT/β‐catenin pathway. Meanwhile, homoharringtoni...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10323884/ https://www.ncbi.nlm.nih.gov/pubmed/36567628 http://dx.doi.org/10.1002/1878-0261.13368 |
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author | Qian, Yu Zhang, Xiang Mao, Shihui Wei, Wenwen Lin, Xiangjie Ling, Qing Ye, Wenle Li, Fenglin Pan, Jiajia Zhou, Yutong Zhao, Yanchun Huang, Xin Huang, Jiansong Tong, Hongyan Sun, Jie Jin, Jie |
author_facet | Qian, Yu Zhang, Xiang Mao, Shihui Wei, Wenwen Lin, Xiangjie Ling, Qing Ye, Wenle Li, Fenglin Pan, Jiajia Zhou, Yutong Zhao, Yanchun Huang, Xin Huang, Jiansong Tong, Hongyan Sun, Jie Jin, Jie |
author_sort | Qian, Yu |
collection | PubMed |
description | Bromodomain‐containing protein 4 (BRD4) inhibitors have been clinically developed to treat acute myeloid leukemia (AML), but their application is limited by the possibility of drug resistance, which is reportedly associated with the activation of the WNT/β‐catenin pathway. Meanwhile, homoharringtonine (HHT), a classic antileukemia drug, possibly inhibits the WNT/β‐catenin pathway. In this study, we attempted to combine a novel BRD4 inhibitor (ACC010) and HHT to explore their synergistic lethal effects in treating AML. Here, we found that co‐treatment with ACC010 and HHT synergistically inhibited cell proliferation, induced apoptosis, and arrested the cell cycle in FMS‐like tyrosine kinase 3‐internal tandem duplication (FLT3‐ITD)–positive AML cells in vitro, and significantly inhibiting AML progression in vivo. Mechanistically, ACC010 and HHT cooperatively downregulated MYC and inhibited FLT3 activation. Further, when HHT was added, ACC010‐resistant cells demonstrated a good synergy. We also extended our study to the mouse BaF3 cell line with FLT3‐inhibitor‐resistant FLT3‐ITD/tyrosine kinase domain mutations and AML cells without FLT3‐ITD. Collectively, our results suggested that the combination treatment of ACC010 and HHT might be a promising strategy for AML patients, especially those carrying FLT3‐ITD. |
format | Online Article Text |
id | pubmed-10323884 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-103238842023-07-07 ACC010, a novel BRD4 inhibitor, synergized with homoharringtonine in acute myeloid leukemia with FLT3 ‐ITD Qian, Yu Zhang, Xiang Mao, Shihui Wei, Wenwen Lin, Xiangjie Ling, Qing Ye, Wenle Li, Fenglin Pan, Jiajia Zhou, Yutong Zhao, Yanchun Huang, Xin Huang, Jiansong Tong, Hongyan Sun, Jie Jin, Jie Mol Oncol Research Articles Bromodomain‐containing protein 4 (BRD4) inhibitors have been clinically developed to treat acute myeloid leukemia (AML), but their application is limited by the possibility of drug resistance, which is reportedly associated with the activation of the WNT/β‐catenin pathway. Meanwhile, homoharringtonine (HHT), a classic antileukemia drug, possibly inhibits the WNT/β‐catenin pathway. In this study, we attempted to combine a novel BRD4 inhibitor (ACC010) and HHT to explore their synergistic lethal effects in treating AML. Here, we found that co‐treatment with ACC010 and HHT synergistically inhibited cell proliferation, induced apoptosis, and arrested the cell cycle in FMS‐like tyrosine kinase 3‐internal tandem duplication (FLT3‐ITD)–positive AML cells in vitro, and significantly inhibiting AML progression in vivo. Mechanistically, ACC010 and HHT cooperatively downregulated MYC and inhibited FLT3 activation. Further, when HHT was added, ACC010‐resistant cells demonstrated a good synergy. We also extended our study to the mouse BaF3 cell line with FLT3‐inhibitor‐resistant FLT3‐ITD/tyrosine kinase domain mutations and AML cells without FLT3‐ITD. Collectively, our results suggested that the combination treatment of ACC010 and HHT might be a promising strategy for AML patients, especially those carrying FLT3‐ITD. John Wiley and Sons Inc. 2023-01-21 /pmc/articles/PMC10323884/ /pubmed/36567628 http://dx.doi.org/10.1002/1878-0261.13368 Text en © 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Articles Qian, Yu Zhang, Xiang Mao, Shihui Wei, Wenwen Lin, Xiangjie Ling, Qing Ye, Wenle Li, Fenglin Pan, Jiajia Zhou, Yutong Zhao, Yanchun Huang, Xin Huang, Jiansong Tong, Hongyan Sun, Jie Jin, Jie ACC010, a novel BRD4 inhibitor, synergized with homoharringtonine in acute myeloid leukemia with FLT3 ‐ITD |
title |
ACC010, a novel BRD4 inhibitor, synergized with homoharringtonine in acute myeloid leukemia with FLT3
‐ITD
|
title_full |
ACC010, a novel BRD4 inhibitor, synergized with homoharringtonine in acute myeloid leukemia with FLT3
‐ITD
|
title_fullStr |
ACC010, a novel BRD4 inhibitor, synergized with homoharringtonine in acute myeloid leukemia with FLT3
‐ITD
|
title_full_unstemmed |
ACC010, a novel BRD4 inhibitor, synergized with homoharringtonine in acute myeloid leukemia with FLT3
‐ITD
|
title_short |
ACC010, a novel BRD4 inhibitor, synergized with homoharringtonine in acute myeloid leukemia with FLT3
‐ITD
|
title_sort | acc010, a novel brd4 inhibitor, synergized with homoharringtonine in acute myeloid leukemia with flt3
‐itd |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10323884/ https://www.ncbi.nlm.nih.gov/pubmed/36567628 http://dx.doi.org/10.1002/1878-0261.13368 |
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