Andrographolide sensitizes glioma to temozolomide by inhibiting DKK1 expression

• Published in: British journal of cancer Vol. 131; no. 8; pp. 1387 - 1398
• Main Authors: Zhang, Zhan-Sheng, Gao, Zi-Xuan, He, Jin-Jin, Ma, Can, Tao, Hang-Tian, Zhu, Feng-Yi, Cheng, Yu-Na, Xie, Cui-Qing, Li, Ji-Qin, Liu, Zhuang-Zhuang, Hou, Li-Li, Sun, Hua, Xie, Song-Qiang, Fang, Dong
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2024; Nature Publishing Group
• Subjects: 1-Phosphatidylinositol 3-kinase; 631/67/1059/99; 631/67/1922; AKT protein; Animals; Antineoplastic Agents, Alkylating - pharmacology; Antineoplastic Agents, Alkylating - therapeutic use; Antitumor agents; Bioluminescence; Biomedical and Life Sciences; Biomedicine; Blood-brain barrier; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - metabolism; Brain cancer; Brain Neoplasms - drug therapy; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Brain tumors; Cancer Research; Cell activation; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Diterpenes - pharmacology; Diterpenes - therapeutic use; Dkk1 protein; Drug Resistance; Drug Synergism; Epidemiology; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - genetics; Gene Expression Regulation, Neoplastic - drug effects; Glioma; Glioma - drug therapy; Glioma - genetics; Glioma - metabolism; Glioma - pathology; Glioma cells; Humans; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Magnetic resonance imaging; Mice; Mice, Nude; Molecular Medicine; Neuroimaging; Oncology; Signal Transduction - drug effects; Temozolomide; Temozolomide - pharmacology; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0007-0920; 1532-1827; 1532-1827
• DOI: 10.1038/s41416-024-02842-0

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.