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...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-07-01
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| Series: | Molecular Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/1878-0261.13368 |
| _version_ | 1797786085962547200 |
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| author | Yu Qian Xiang Zhang Shihui Mao Wenwen Wei Xiangjie Lin Qing Ling Wenle Ye Fenglin Li Jiajia Pan Yutong Zhou Yanchun Zhao Xin Huang Jiansong Huang Hongyan Tong Jie Sun Jie Jin |
| author_facet | Yu Qian Xiang Zhang Shihui Mao Wenwen Wei Xiangjie Lin Qing Ling Wenle Ye Fenglin Li Jiajia Pan Yutong Zhou Yanchun Zhao Xin Huang Jiansong Huang Hongyan Tong Jie Sun Jie Jin |
| author_sort | Yu Qian |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-13T01:03:05Z |
| format | Article |
| id | doaj.art-7f0d9b974eba45f3bf711e128520966a |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-03-13T01:03:05Z |
| publishDate | 2023-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj.art-7f0d9b974eba45f3bf711e128520966a2023-07-06T09:54:22ZengWileyMolecular Oncology1574-78911878-02612023-07-011771402141810.1002/1878-0261.13368ACC010, a novel BRD4 inhibitor, synergized with homoharringtonine in acute myeloid leukemia with FLT3‐ITDYu Qian0Xiang Zhang1Shihui Mao2Wenwen Wei3Xiangjie Lin4Qing Ling5Wenle Ye6Fenglin Li7Jiajia Pan8Yutong Zhou9Yanchun Zhao10Xin Huang11Jiansong Huang12Hongyan Tong13Jie Sun14Jie Jin15Department of Hematology, The First Affiliated Hospital Zhejiang University School of Medicine Hangzhou ChinaDepartment of Hematology, The First Affiliated Hospital Zhejiang University School of Medicine Hangzhou ChinaDepartment of Hematology, The First Affiliated Hospital Zhejiang University School of Medicine Hangzhou ChinaDepartment of Hematology, The First Affiliated Hospital Zhejiang University School of Medicine Hangzhou ChinaDepartment of Hematology, The First Affiliated Hospital Zhejiang University School of Medicine Hangzhou ChinaZhejiang Provincial Key Laboratory of Hematopoietic Malignancy Zhejiang University Hangzhou ChinaDepartment of Hematology, The First Affiliated Hospital Zhejiang University School of Medicine Hangzhou ChinaThe Affiliated People's Hospital of Ningbo University ChinaDepartment of Hematology, The First Affiliated Hospital Zhejiang University School of Medicine Hangzhou ChinaDepartment of Hematology, The First Affiliated Hospital Zhejiang University School of Medicine Hangzhou ChinaDepartment of Hematology, The First Affiliated Hospital Zhejiang University School of Medicine Hangzhou ChinaDepartment of Hematology, The First Affiliated Hospital Zhejiang University School of Medicine Hangzhou ChinaDepartment of Hematology, The First Affiliated Hospital Zhejiang University School of Medicine Hangzhou ChinaDepartment of Hematology, The First Affiliated Hospital Zhejiang University School of Medicine Hangzhou ChinaDepartment of Hematology, The First Affiliated Hospital Zhejiang University School of Medicine Hangzhou ChinaDepartment of Hematology, The First Affiliated Hospital Zhejiang University School of Medicine Hangzhou ChinaBromodomain‐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.https://doi.org/10.1002/1878-0261.13368acute myeloid leukemiaFLT3‐ITDhomoharringtoninenovel BRD4 Inhibitor ACC010 |
| spellingShingle | Yu Qian Xiang Zhang Shihui Mao Wenwen Wei Xiangjie Lin Qing Ling Wenle Ye Fenglin Li Jiajia Pan Yutong Zhou Yanchun Zhao Xin Huang Jiansong Huang Hongyan Tong Jie Sun Jie Jin ACC010, a novel BRD4 inhibitor, synergized with homoharringtonine in acute myeloid leukemia with FLT3‐ITD Molecular Oncology acute myeloid leukemia FLT3‐ITD homoharringtonine novel BRD4 Inhibitor ACC010 |
| 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 | acute myeloid leukemia FLT3‐ITD homoharringtonine novel BRD4 Inhibitor ACC010 |
| url | https://doi.org/10.1002/1878-0261.13368 |
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