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Andrographolide sensitizes glioma to temozolomide by inhibiting DKK1 expression
Zhan-Sheng Zhang1,2, Zi-Xuan Gao1,2, Jin-Jin He1
1Department of Pharmacy, The First Afffliated Hospital of Henan University, N. Jinming Ave, Kaifeng, 475004, China.
Background:
Temozolomide (TMZ) is the first-line chemotherapeutic drug for gliomas treatment. However, the clinical efficacy of TMZ in glioma patients was very limited. Therefore, it is urgently needed to discover a novel approach to increase the sensitivity of glioma cells to TMZ.
Methods:
Western blot, immunohistochemical staining, and qRT-PCR assays were used to explore the mechanisms underlying TMZ promoting DKK1 expression and andrographolide (AND) inhibiting DKK1 expression. HPLC was used to detect the ability of andrographolide (AND) to penetrate the blood-brain barrier. MTT assay, bioluminescence images, magnetic resonance imaging (MRI) and H&E staining were employed to measure the proliferative activity of glioma cells and the growth of intracranial tumors.
Results:
TMZ can promote DKK1 expression in glioma cells and brain tumors of an orthotopic model of glioma. DKK1 could promote glioma cell proliferation and tumor growth in an orthotopic model of glioma. Mechanistically, TMZ increased EGFR expression and subsequently induced the activation of its downstream MEK-ERK and PI3K-Akt pathways, thereby promoting DKK1 expression in glioma cells. Andrographolide inhibited TMZ-induced DKK1 expression through inactivating MEK-ERK and PI3K-Akt pathways. Andrographolide can cross the blood-brain barrier, the combination of TMZ and andrographolide not only improved the anti-tumor effects of TMZ but also showed a survival benefit in an orthotopic model of glioma.
Conclusion:
Andrographolide can enhance anti-tumor activity of TMZ against glioma by inhibiting DKK1 expression.
Insights
Andrographolide enhances temozolomide (TMZ) efficacy in glioma treatment by inhibiting DKK1 expression. This combination therapy improves anti-tumor effects and survival in preclinical models.
Area of Science:
- Neuro-oncology
- Pharmacology
- Molecular Biology
Background:
- Temozolomide (TMZ) is a first-line chemotherapy for gliomas, but its clinical efficacy is limited.
- There is a critical need for novel strategies to overcome TMZ resistance in glioma patients.
Purpose of the Study:
- To investigate the role of DKK1 in TMZ-mediated glioma progression.
- To evaluate andrographolide (AND) as a sensitizer to TMZ in glioma treatment.
Main Methods:
- Western blot, qRT-PCR, and immunohistochemistry to analyze DKK1 expression.
- In vivo studies using orthotopic glioma models to assess tumor growth and survival.
- HPLC to determine blood-brain barrier penetration of andrographolide.
Main Results:
- TMZ treatment increased DKK1 expression in glioma cells and tumors, promoting proliferation.
- Andrographolide inhibited TMZ-induced DKK1 expression by targeting EGFR-downstream pathways (MEK-ERK, PI3K-Akt).
- Combined TMZ and andrographolide demonstrated enhanced anti-tumor activity and improved survival in preclinical glioma models.
Conclusions:
- Andrographolide enhances the anti-tumor activity of temozolomide against gliomas.
- Inhibition of DKK1 expression is a key mechanism by which andrographolide sensitizes glioma cells to TMZ.
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