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Minnelide exhibits antileukemic activity by targeting the Ars2/miR-190a-3p axis
Liang Yuan1, Xiuxing Jiang2, Guanfei Jia2
1Key Laboratory of Basic Pharmacology of Ministry of Education, Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563006, PR China.
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.
Insights
Minnelide effectively treats acute leukemia by targeting Ars2 and miR-190a-3p signaling, inducing cell cycle arrest and apoptosis. This novel strategy warrants further clinical evaluation for leukemia treatment.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Acute leukemia (AL) requires novel therapeutic strategies.
- Minnelide, a triptolide prodrug, shows antileukemic potential but its mechanism is unknown.
- Understanding minnelide's action is crucial for its clinical application.
Purpose of the Study:
- To elucidate the molecular mechanisms of minnelide's antileukemic activity.
- To identify key molecular targets and pathways involved in minnelide's efficacy.
- To validate minnelide as a potential therapeutic agent for acute leukemia.
Main Methods:
- Utilized acute leukemia cell lines, primary human leukemia cells, and a xenograft mouse model.
- Treated models with triptolide and minnelide.
- Employed western blotting, immunoprecipitation, flow cytometry, GSEA, and LC-MS for mechanistic analysis.
Main Results:
- Minnelide demonstrated significant inhibition of leukemogenesis and improved survival in AL mouse models.
- Triptolide induced G1 cell cycle arrest and apoptosis in human AL cells.
- Identified Ars2 as a direct target of triptolide, leading to miR-190a-3p downregulation, PTEN/Akt pathway disruption, and subsequent cell cycle arrest and apoptosis.
Conclusions:
- Targeting Ars2/miR-190a-3p signaling with minnelide presents a novel chemotherapeutic strategy for AL.
- Minnelide's mechanism involves direct targeting of Ars2, impacting crucial signaling pathways.
- Findings support further clinical investigation of minnelide for acute leukemia treatment.
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