Minnelide exhibits antileukemic activity by targeting the Ars2/miR-190a-3p axis.
Phytomedicine
; 130: 155724, 2024 Jul 25.
Article
en En
| MEDLINE
| ID: mdl-38759317
ABSTRACT
BACKGROUND:
The identification of a novel and effective strategy for the clinical treatment of acute leukemia (AL) is a long-term goal. Minnelide, a water-soluble prodrug of triptolide, has recently been evaluated in phase I and II clinical trials in patients with multiple cancers and has shown promise as an antileukemic agent. However, the molecular mechanism underlying minnelide's antileukemic activity remains unclear.PURPOSE:
To explore the molecular mechanisms by which minnelide exhibits antileukemic activity.METHODS:
AL cells, primary human leukemia cells, and a xenograft mouse model were treated with triptolide and minnelide. The molecular mechanism was elucidated using western blotting, immunoprecipitation, flow cytometry, GSEA and liquid chromatography-mass spectrometry analysis.RESULTS:
Minnelide was highly effective in inhibiting leukemogenesis and improving survival in two complementary AL mouse models. Triptolide, an active form of minnelide, causes cell cycle arrest in G1 phase and induces apoptosis in both human AL cell lines and primary AL cells. Mechanistically, we identified Ars2 as a new chemotherapeutic target of minnelide for AL treatment. We found that triptolide directly targeted Ars2, resulting in the downregulation of miR-190a-3p, which led to the disturbance of PTEN/Akt signaling and culminated in G1 cell cycle arrest and apoptosis.CONCLUSIONS:
Our findings demonstrate that targeting Ars2/miR-190a-3p signaling using minnelide could represent a novel chemotherapeutic strategy for AL treatment and support the evaluation of minnelide for the treatment of AL in clinical trials.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Fenantrenos
/
Apoptosis
/
MicroARNs
/
Diterpenos
/
Compuestos Epoxi
Límite:
Animals
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Humans
Idioma:
En
Revista:
Phytomedicine
Asunto de la revista:
TERAPIAS COMPLEMENTARES
Año:
2024
Tipo del documento:
Article