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Translational Therapeutics

Andrographolide sensitizes glioma to temozolomide by inhibiting DKK1 expression

British Journal of Cancer (2024)Cite this article

Subjects

Abstract

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.

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Fig. 1: Temozolomide promotes DKK1 expression in both glioma cells and glioma model of mice.
Fig. 2: DKK1 is a sensitizing target for TMZ in glioma.
Fig. 3: EGFR-mediated MEK-ERK and PI3K-Akt pathways are involved in TMZ-induced DKK1 expression in glioma.
Fig. 4: Andrographolide inhibits DKK1 expression but has no effects on EGFR expression in glioma cells.
Fig. 5: Andrographolide alleviates DKK1 expression through inhibiting MEK-ERK and PI3K-Akt pathways in glioma cells.
Fig. 6: Andrographolide enhances the antitumor effect of temozolomide by inhibiting DKK1 in an orthotopic model of glioma.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

This study was supported by the National Key R&D Program of China (2021YFA0909600), Natural Science Foundation of Henan (232300420050), Key projects of Henan Science and Technology Department (232102311115, 242102311032, 242102311072). This work was also supported by the Open Projects in the Key Laboratory for Neuroscience of Peking University.

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Author notes

  1. These authors contributed equally: Zhan-Sheng Zhang, Zi-Xuan Gao, Jin-Jin He.

Authors and Affiliations

  1. Department of Pharmacy, The First Afffliated Hospital of Henan University, N. Jinming Ave, Kaifeng, 475004, China

    Zhan-Sheng Zhang, Zi-Xuan Gao, Jin-Jin He, Song-Qiang Xie & Dong Fang

  2. Institute of Chemical Biology, School of Pharmacy, Henan University, N. Jinming Ave, Kaifeng, 475004, China

    Zhan-Sheng Zhang, Zi-Xuan Gao, Can Ma, Hang-Tian Tao, Feng-Yi Zhu, Yu-Na Cheng, Cui-Qing Xie, Ji-Qin Li, Zhuang-Zhuang Liu, Li-Li Hou, Hua Sun, Song-Qiang Xie & Dong Fang

  3. Henan Province Engineering Research Center of High Value Utilization to Natural Medical Resource in Yellow River Basin, Kaifeng, 475004, China

    Song-Qiang Xie & Dong Fang

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Contributions

ZSZ, ZXG, JJH, CM, HTT, FYZ, YNC, CQX, JQL, and ZZL carried out the experiments, LLH and HS performed the data analysis, SQX and DF designed this study and wrote the manuscript.

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Correspondence to Hua Sun, Song-Qiang Xie or Dong Fang.

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Zhang, ZS., Gao, ZX., He, JJ. et al. Andrographolide sensitizes glioma to temozolomide by inhibiting DKK1 expression. Br J Cancer (2024). https://doi.org/10.1038/s41416-024-02842-0

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