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Daurisoline suppress glioma progression by inhibiting autophagy through PI3K/AKT/mTOR pathway and increases TMZ
Hai-Tang Yin1, Hui-Lu1, Ji-Hong Yang1
1Department of Pharmacy, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou Province, PR China; College of Pharmacy, Guizhou Medical University, Guiyang, Guizhou Province, PR China.
Abstract:
Glioma is one of the most common primary malignant tumors of the central nervous system. Temozolomide (TMZ) is the only effective chemotherapeutic agent, but it easily develops resistance and has unsatisfactory efficacy. Consequently, there is an urgent need to develop safe and effective compounds for glioma treatment. The cytotoxicity of 30 candidate compounds to glioma cells was detected by the CCK-8 assay. Daurisoline (DAS) was selected for further investigation due to its potent anti-glioma effects. Our study revealed that DAS induced glioma cell apoptosis through increasing caspase-3/6/9 activity. DAS significantly inhibited the proliferation of glioma cells by inducing G1-phase cell cycle arrest. Meanwhile, DAS remarkably suppressed the migration and invasion of glioma cells by regulating epithelial-mesenchymal transition. Mechanistically, our results revealed that DAS impaired the autophagic flux of glioma cells at a late stage by mediating the PI3K/AKT/mTOR pathway. DAS could inhibit TMZ-induced autophagy and then significantly promote TMZ chemosensitivity. Nude mice xenograft model revealed that DAS could restrain glioma proliferation and promote TMZ chemosensitivity. Thus, DAS is a potential anti-glioma drug that can improve glioma sensitivity to TMZ and provide a new therapeutic strategy for glioma in chemoresistance.
Insights
Daurisoline (DAS) shows potent anti-glioma effects by inducing apoptosis and cell cycle arrest. It also enhances temozolomide (TMZ) efficacy by inhibiting autophagy, offering a new strategy for chemoresistant glioma.
Area of Science:
- Neuro-oncology
- Cancer Biology
- Pharmacology
Background:
- Glioma is a common primary malignant brain tumor.
- Temozolomide (TMZ) is a standard chemotherapy with limited efficacy due to resistance.
- Novel therapeutic agents are needed for effective glioma treatment.
Purpose of the Study:
- To investigate the anti-glioma effects of Daurisoline (DAS).
- To explore DAS's mechanism of action in glioma cells.
- To evaluate DAS's potential to overcome temozolomide resistance.
Main Methods:
- Cytotoxicity screening of 30 compounds using CCK-8 assay.
- Assessment of apoptosis, cell cycle, migration, and invasion.
- Analysis of the PI3K/AKT/mTOR pathway and autophagy.
- In vivo efficacy study using a nude mice xenograft model.
Main Results:
- Daurisoline (DAS) demonstrated potent cytotoxicity against glioma cells.
- DAS induced apoptosis via caspase activation and G1 cell cycle arrest.
- DAS suppressed glioma cell migration and invasion by regulating epithelial-mesenchymal transition.
- DAS impaired late-stage autophagic flux through the PI3K/AKT/mTOR pathway.
- DAS inhibited TMZ-induced autophagy, enhancing TMZ chemosensitivity.
- In vivo studies confirmed DAS restrains glioma proliferation and improves TMZ chemosensitivity.
Conclusions:
- Daurisoline (DAS) exhibits significant anti-glioma activity.
- DAS enhances the efficacy of temozolomide (TMZ) in chemoresistant glioma models.
- DAS represents a promising therapeutic candidate for glioma treatment.
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