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EGCG inhibits properties of glioma stem-like cells and synergizes with temozolomide through downregulation of P-glycoprotein inhibition

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Abstract

Rational: Combination therapy to inhibit cancer stem cells may have important clinical implications. Here, we examine the molecular mechanisms by which epigallocatechin gallate (EGCG), a bioactive polyphenol in green tea, inhibits the stem cell characteristics of glioma stem-like cells (GSLCs) and synergizes with temozolomide (TMZ), a DNA-methylating agent commonly used as first-line chemotherapy in gliomas. GSLCs were enriched from the human glioblastoma cell line U87 using neurosphere culture. Cells were analyzed using flow cytometry, quantitative PCR, and western blotting. Compared to U87 cells, a higher percentage of U87 GSLCs remained in the G0/G1 phase, with downregulation of the cell-cycle protein CylinD1 and overexpression of stem cell markers CD133 and ALDH1. The drug-resistance gene ABCB1 (but not ABCG2 or MGMT) also showed high mRNA and protein expression. The resistance index of U87 GSLCs against TMZ and carmustine (BCNU) was 3.0 and 16.8, respectively. These results indicate that U87 GSLCs possess neural stem cell and drug-resistance properties. Interestingly, EGCG treatment inhibited cell viability, neurosphere formation, and migration in this cell model. EGCG also induced apoptosis, downregulation of p-Akt and Bcl-2, and cleaving PARP in a dose-dependent manner. Importantly, EGCG treatment significantly downregulated P-glycoprotein expression but not that of ABCG2 or MGMT and simultaneously enhanced sensitivity to TMZ. Our study demonstrates that the use of EGCG alone or in combination with TMZ may be an effective therapeutic strategy for glioma.

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (No. 81072059, 31201028, 81201727), the Science and Technology Innovation Key Project of Guangdong Higher Education Institutes (No. CXZD1110).

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The authors declare that no competing interests exist.

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Authors and Affiliations

  1. Department of Pathology, Medical School of Jinan University, Guangzhou, 510632, People’s Republic of China

    Yong Zhang, Shao-Xiang Wang, Ji-Wei Ma, Hai-Ying Li, Jie-Cheng Ye, Si-Ming Xie, Bin Du & Xue-Yun Zhong

  2. Guangdong Province Key Laboratory of Molecule Immunology and Antibody Engineering, Jinan University, Guangzhou, 510632, China

    Yong Zhang, Shao-Xiang Wang, Ji-Wei Ma, Hai-Ying Li, Jie-Cheng Ye, Si-Ming Xie, Bin Du & Xue-Yun Zhong

  3. School of Medicine, Shenzhen University, Shenzhen, 518060, China

    Shao-Xiang Wang

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  1. Yong Zhang
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Correspondence to Bin Du or Xue-Yun Zhong.

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Yong Zhang and Shao-Xiang Wang contributed equally to this study.

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Zhang, Y., Wang, SX., Ma, JW. et al. EGCG inhibits properties of glioma stem-like cells and synergizes with temozolomide through downregulation of P-glycoprotein inhibition. J Neurooncol 121, 41–52 (2015). https://doi.org/10.1007/s11060-014-1604-1

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