Berberine reduces temozolomide resistance by inducing autophagy via the ERK1/2 signaling pathway in glioblastoma

Huiling Qu,Zhuyin Song,Jiao Wu,Xin Gao,Xin Jiang,Xiaofu Song,Zhicheng Yao,Li Na,Lijuan Bai

doi:10.1186/s12935-020-01693-y

Huiling Qu, Zhuyin Song + Show 7 more

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https://doi.org/10.1186/s12935-020-01693-y

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Abstract

BackgroundThe ability to treat glioblastoma (GBM) using the chemotherapeutic agent temozolomide (TMZ) has been hampered by the development of therapeutic resistance. In this study, we assessed the ability of the isoquinoline alkaloid berberine to alter GBM TMZ resistance using two different TMZ-resistant cell lines to mimic a physiologically relevant GBM experimental system.MethodsBy treating these resistant cell lines with berberine followed by TMZ, we were able to assess the chemosensitivity of these cells and their parental strains, based on their performance in the MTT and colony formation assays, as well as on the degree of detectable apoptosis that was detected in the strains. Furthermore, we used Western blotting to assess autophagic responses in these cell lines, and we extended this work into a xenograft mouse model to assess the in vivo efficacy of berberine.ResultsThrough these experiments, our findings indicated that berberine enhanced autophagy and apoptosis in TMZ-resistant cells upon TMZ treatment in a manner that was linked with ERK1/2 signaling. Similarly, when used in vivo, berberine increased GBM sensitivity to TMZ through ERK1/2 signaling pathways.ConclusionsThese findings demonstrate that berberine is an effective method of increasing the sensitization of GBM cells to TMZ treatment in a manner that is dependent upon the ERK1/2-mediated induction of autophagy, thus making berberine a potentially viable therapeutic agent for GBM treatment.

Highlights

Of all the types of primary brain tumors affecting adults, glioblastoma (GBM) remains the deadliest [1, 2]
To determine whether berberine could alter the sensitivities of these cell lines to TMZ, the two TMZ-R lines were treated with berberine and assessed via MTT and colony formation assays upon the TMZ treatment
Berberine-treated U87/TMZ-R and U251/TMZ-R cells performed worse in response to the colony formation assays (Additional file 1: Figure S1C, D), and we confirmed the elevated rates of apoptosis in these cells by the (See figure on page.) Fig. 1 Berberine resensitizes TMZ resistance cells to TMZ in GBM cells. a and b Parental and TMZ resistance cells were treated with increasing concentrations of TMZ for 24, 48 72 h

Summary

Introduction

Of all the types of primary brain tumors affecting adults, glioblastoma (GBM) remains the deadliest [1, 2]. The identification of novel strategies that are sufficient in altering autophagic responses for the treatment with chemotherapeutic compounds, such as TMZ, may be a viable strategy to reduce chemoresistance in GBM patients. A number of therapeutic properties have been attributed to berberine (in the context of cancer treatment), with such properties including the promotion of the induction of apoptosis in tumor cells and the further mediation of the growth arrest of tumor cells [21, 22]. The ability to treat glioblastoma (GBM) using the chemotherapeutic agent temozolomide (TMZ) has been hampered by the development of therapeutic resistance. We assessed the ability of the isoquinoline alkaloid berberine to alter GBM TMZ resistance using two different TMZ-resistant cell lines to mimic a physiologically relevant GBM experimental system

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