Pharmacological targeting of type phosphodiesterase 4 inhibits the development of acute myeloid leukemia by impairing mitochondrial function through the Wnt/β-catenin pathway
Acute myeloid leukemia (AML) is prone to drug-resistant relapse with a low 5-year survival rate. New therapeutic modalities are sorely needed to provide hope for AML relapse patients. Herein, we demonstrated a specific inhibitor of type 4 phosphodiesterase (PDE4), Zl-n-91, could significantly reduce...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-01-01
|
| Series: | Biomedicine & Pharmacotherapy |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0753332222014160 |
| _version_ | 1811299683471982592 |
|---|---|
| author | Ping Mao Changhao Huang Yuyu Li Yuanyi Zhao Sujin Zhou Zhenggang Zhao Yunping Mu Lina Wang Fanghong Li Allan Z. Zhao |
| author_facet | Ping Mao Changhao Huang Yuyu Li Yuanyi Zhao Sujin Zhou Zhenggang Zhao Yunping Mu Lina Wang Fanghong Li Allan Z. Zhao |
| author_sort | Ping Mao |
| collection | DOAJ |
| description | Acute myeloid leukemia (AML) is prone to drug-resistant relapse with a low 5-year survival rate. New therapeutic modalities are sorely needed to provide hope for AML relapse patients. Herein, we demonstrated a specific inhibitor of type 4 phosphodiesterase (PDE4), Zl-n-91, could significantly reduce the proliferation of AML cells, block DNA replication process, and increase AML cell death. Zl-n-91 also impeded the growth of subcutaneous xenograft and prolonged the survival of the MLL-AF9-driven AML model. Bioinformatic analysis revealed that elevated mitochondrial gene signatures inversely correlate with the survival of AML patients; and importantly, Zl-n-91 strongly suppressed the function of mitochondria. In addition, this PDE4 inhibitor induced alterations in multiple signaling pathways, including the reduction of β-catenin activity. Stimulation of the Wnt/β-catenin pathway could attenuate the inhibitory effect of Zl-n-91 on AML cell proliferation as well as mitochondrial function. Taken together, we revealed for the first time that targeting PDE4 activity could attenuate mitochondrial function through a Wnt/β-catenin pathway, which in turn would block the growth of AML cells. Specific PDE4 inhibitors can potentially serve as a new treatment modality for AML patients. |
| first_indexed | 2024-04-13T06:40:25Z |
| format | Article |
| id | doaj.art-9ba197750efc4a2bb762b85db21d931c |
| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-04-13T06:40:25Z |
| publishDate | 2023-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-9ba197750efc4a2bb762b85db21d931c2022-12-22T02:57:46ZengElsevierBiomedicine & Pharmacotherapy0753-33222023-01-01157114027Pharmacological targeting of type phosphodiesterase 4 inhibits the development of acute myeloid leukemia by impairing mitochondrial function through the Wnt/β-catenin pathwayPing Mao0Changhao Huang1Yuyu Li2Yuanyi Zhao3Sujin Zhou4Zhenggang Zhao5Yunping Mu6Lina Wang7Fanghong Li8Allan Z. Zhao9School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Xiaoguwei Street, Panyu District, Guangzhou, Guangdong 510006, ChinaSchool of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Xiaoguwei Street, Panyu District, Guangzhou, Guangdong 510006, ChinaSchool of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Xiaoguwei Street, Panyu District, Guangzhou, Guangdong 510006, ChinaSchool of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Xiaoguwei Street, Panyu District, Guangzhou, Guangdong 510006, ChinaSchool of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Xiaoguwei Street, Panyu District, Guangzhou, Guangdong 510006, ChinaSchool of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Xiaoguwei Street, Panyu District, Guangzhou, Guangdong 510006, ChinaSchool of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Xiaoguwei Street, Panyu District, Guangzhou, Guangdong 510006, ChinaSchool of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Xiaoguwei Street, Panyu District, Guangzhou, Guangdong 510006, ChinaCorresponding authors.; School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Xiaoguwei Street, Panyu District, Guangzhou, Guangdong 510006, ChinaCorresponding authors.; School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Xiaoguwei Street, Panyu District, Guangzhou, Guangdong 510006, ChinaAcute myeloid leukemia (AML) is prone to drug-resistant relapse with a low 5-year survival rate. New therapeutic modalities are sorely needed to provide hope for AML relapse patients. Herein, we demonstrated a specific inhibitor of type 4 phosphodiesterase (PDE4), Zl-n-91, could significantly reduce the proliferation of AML cells, block DNA replication process, and increase AML cell death. Zl-n-91 also impeded the growth of subcutaneous xenograft and prolonged the survival of the MLL-AF9-driven AML model. Bioinformatic analysis revealed that elevated mitochondrial gene signatures inversely correlate with the survival of AML patients; and importantly, Zl-n-91 strongly suppressed the function of mitochondria. In addition, this PDE4 inhibitor induced alterations in multiple signaling pathways, including the reduction of β-catenin activity. Stimulation of the Wnt/β-catenin pathway could attenuate the inhibitory effect of Zl-n-91 on AML cell proliferation as well as mitochondrial function. Taken together, we revealed for the first time that targeting PDE4 activity could attenuate mitochondrial function through a Wnt/β-catenin pathway, which in turn would block the growth of AML cells. Specific PDE4 inhibitors can potentially serve as a new treatment modality for AML patients.http://www.sciencedirect.com/science/article/pii/S0753332222014160PDE4LeukemiaAMLMitochondriaWNT/β-catenin |
| spellingShingle | Ping Mao Changhao Huang Yuyu Li Yuanyi Zhao Sujin Zhou Zhenggang Zhao Yunping Mu Lina Wang Fanghong Li Allan Z. Zhao Pharmacological targeting of type phosphodiesterase 4 inhibits the development of acute myeloid leukemia by impairing mitochondrial function through the Wnt/β-catenin pathway Biomedicine & Pharmacotherapy PDE4 Leukemia AML Mitochondria WNT/β-catenin |
| title | Pharmacological targeting of type phosphodiesterase 4 inhibits the development of acute myeloid leukemia by impairing mitochondrial function through the Wnt/β-catenin pathway |
| title_full | Pharmacological targeting of type phosphodiesterase 4 inhibits the development of acute myeloid leukemia by impairing mitochondrial function through the Wnt/β-catenin pathway |
| title_fullStr | Pharmacological targeting of type phosphodiesterase 4 inhibits the development of acute myeloid leukemia by impairing mitochondrial function through the Wnt/β-catenin pathway |
| title_full_unstemmed | Pharmacological targeting of type phosphodiesterase 4 inhibits the development of acute myeloid leukemia by impairing mitochondrial function through the Wnt/β-catenin pathway |
| title_short | Pharmacological targeting of type phosphodiesterase 4 inhibits the development of acute myeloid leukemia by impairing mitochondrial function through the Wnt/β-catenin pathway |
| title_sort | pharmacological targeting of type phosphodiesterase 4 inhibits the development of acute myeloid leukemia by impairing mitochondrial function through the wnt β catenin pathway |
| topic | PDE4 Leukemia AML Mitochondria WNT/β-catenin |
| url | http://www.sciencedirect.com/science/article/pii/S0753332222014160 |
| work_keys_str_mv | AT pingmao pharmacologicaltargetingoftypephosphodiesterase4inhibitsthedevelopmentofacutemyeloidleukemiabyimpairingmitochondrialfunctionthroughthewntbcateninpathway AT changhaohuang pharmacologicaltargetingoftypephosphodiesterase4inhibitsthedevelopmentofacutemyeloidleukemiabyimpairingmitochondrialfunctionthroughthewntbcateninpathway AT yuyuli pharmacologicaltargetingoftypephosphodiesterase4inhibitsthedevelopmentofacutemyeloidleukemiabyimpairingmitochondrialfunctionthroughthewntbcateninpathway AT yuanyizhao pharmacologicaltargetingoftypephosphodiesterase4inhibitsthedevelopmentofacutemyeloidleukemiabyimpairingmitochondrialfunctionthroughthewntbcateninpathway AT sujinzhou pharmacologicaltargetingoftypephosphodiesterase4inhibitsthedevelopmentofacutemyeloidleukemiabyimpairingmitochondrialfunctionthroughthewntbcateninpathway AT zhenggangzhao pharmacologicaltargetingoftypephosphodiesterase4inhibitsthedevelopmentofacutemyeloidleukemiabyimpairingmitochondrialfunctionthroughthewntbcateninpathway AT yunpingmu pharmacologicaltargetingoftypephosphodiesterase4inhibitsthedevelopmentofacutemyeloidleukemiabyimpairingmitochondrialfunctionthroughthewntbcateninpathway AT linawang pharmacologicaltargetingoftypephosphodiesterase4inhibitsthedevelopmentofacutemyeloidleukemiabyimpairingmitochondrialfunctionthroughthewntbcateninpathway AT fanghongli pharmacologicaltargetingoftypephosphodiesterase4inhibitsthedevelopmentofacutemyeloidleukemiabyimpairingmitochondrialfunctionthroughthewntbcateninpathway AT allanzzhao pharmacologicaltargetingoftypephosphodiesterase4inhibitsthedevelopmentofacutemyeloidleukemiabyimpairingmitochondrialfunctionthroughthewntbcateninpathway |