Bufalin enhanced temozolomide efficacy by promoting EGFR protein degradation in glioblastoma

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-06-16 DOI:10.1016/j.phymed.2025.156987

Runze Yu , Yuhan Li , Bo Wang , Yuxuan Guo , Yixi Sun , Yingjie He , Jianhua Xiong , Shulong Jiang , Lei Han

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引用次数: 0

Abstract

Background

Glioblastoma (GBM), the most aggressive form of glioma, is associated with a poor patient prognosis. Temozolomide (TMZ), the first-line chemotherapeutic agent for GBM patients, has its efficacy closely tied to patient prognosis. The epidermal growth factor receptor (EGFR) can affect TMZ efficacy by activating its downstream pathways.

Purpose

This research aimed to explore the potential mechanism of bufalin as a therapeutic agent for GBM.

Methods

The pharmacological mechanism was predicted using network pharmacology, molecular docking, and molecular dynamics simulation, and subsequently validated through in vivo and in vitro studies.

Result

This study found that bufalin, a traditional Chinese medicine, may interact with EGFR and modulate GBM progression. Western blot and immunofluorescence demonstrated that bufalin promoted the EGFR protein degradation through the chaperone-mediated autophagy (CMA). TUNEL, γH₂AX immunofluorescence, and comet assays verified the impact of bufalin on enhancing the efficacy of TMZ in GBM. In a tumor xenograft model, the combination of TMZ and bufalin showed significantly greater efficacy than either agent alone.

Conclusion

Bufalin significantly reduced EGFR protein levels via CMA and enhanced TMZ efficacy in GBM by modulating the EGFR signaling pathway. Pharmacological and molecular biological experimental data indicated that bufalin has great potential as a new drug to enhance the efficacy of TMZ in GBM in the future.

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蟾毒灵通过促进胶质母细胞瘤中EGFR蛋白降解来增强替莫唑胺的疗效

胶质母细胞瘤（GBM）是最具侵袭性的胶质瘤，患者预后较差。替莫唑胺（Temozolomide， TMZ）是GBM患者的一线化疗药物，其疗效与患者预后密切相关。表皮生长因子受体（EGFR）通过激活其下游通路影响TMZ的疗效。目的探讨蟾毒灵治疗GBM的潜在作用机制。方法采用网络药理学、分子对接、分子动力学模拟等方法预测其药理作用机制，并通过体内外实验验证其药理作用机制。结果中药蟾毒灵可能与EGFR相互作用，调节GBM的进展。Western blot和免疫荧光显示蟾毒灵通过伴侣蛋白介导的自噬（CMA）促进EGFR蛋白降解。TUNEL、γ - h2ax免疫荧光和comet实验验证了蟾毒灵对TMZ治疗GBM的增强作用。在异种肿瘤移植模型中，TMZ和蟾毒灵联合使用的疗效明显高于单独使用任何一种药物。结论蟾毒灵通过CMA降低EGFR蛋白水平，通过调节EGFR信号通路增强TMZ治疗GBM的疗效。药理学和分子生物学实验数据表明，蟾毒灵作为一种增强TMZ治疗GBM疗效的新药具有很大的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.