Pharmacological targeting of type phosphodiesterase 4 inhibits the development of acute myeloid leukemia by impairing mitochondrial function through the Wnt/ß-catenin pathway.
Biomed Pharmacother
; 157: 114027, 2023 Jan.
Article
em En
| MEDLINE
| ID: mdl-36436494
ABSTRACT
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 ß-catenin activity. Stimulation of the Wnt/ß-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/ß-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.
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Base de dados:
MEDLINE
Assunto principal:
Leucemia Mieloide Aguda
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Beta Catenina
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article