17ß-neriifolin from unripe fruits of Cerbera manghas suppressed cell proliferation via the inhibition of HOXA9-dependent transcription and the induction of apoptosis in the human AML cell line THP-1.
J Nat Med
; 77(1): 180-187, 2023 Jan.
Article
em En
| MEDLINE
| ID: mdl-36266527
ABSTRACT
Homeobox A9 (HOXA9) is a transcription factor that is overexpressed in acute myeloid leukemia (AML). It is associated with the pathogenesis and progression of AML, and is a factor responsible for a poor prognosis. Therefore, the development of HOXA9-targeting molecules may contribute to not only better understanding of the mechanism of HOXA9 regulation, but also the development of therapeutic applications. We constructed a reporter assay system using the promoter region of the KBTBD10 gene, to which HOXA9 directly binds and regulates transcription, in the human acute monocytic leukemia cell line THP-1. Using this luciferase gene assay, we screened 1120 plant extracts and a methanol extract of the unripe fruits of Cerbera manghas was found to suppress the reporter gene expression mediated by the KBTBD10 promoter. From the extract, five steroid-type compounds were identified as the active constituents 7α-neriifolin (1), 17ß-neriifolin (2), 17α-digitoxigenin ß-D-glucosyl-(1 â 4)-α-L-thevetoside (3), 17ß-digitoxigenin ß-D-glucosyl-(1 â 4)-α-L-thevetoside (4), and acetylthevetin B (5). Among the five compounds, 17ß-neriifolin most potently inhibited HOXA9-dependent gene expression without affecting the HOXA9 mRNA levels, and suppressed cell proliferation by inducing apoptosis. The findings on the structure-activity relationships of the compounds from C. manghas may contribute to the development of small molecule inhibitors of HOXA9.
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Base de dados:
MEDLINE
Assunto principal:
Leucemia Mieloide Aguda
/
Apocynaceae
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article