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The cytotoxic effect of β-elemene against malignant glioma is enhanced by base-excision repair inhibitor methoxyamine

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Abstract

This study investigated the effects of β-elemene + methoxyamine, a DNA base-excision repair inhibitor, on the inhibition of glioma growth. We treated C6 and SHG44 glioma cells with β-elemene and methoxyamine individually or in combinations, and subsequently analyzed cellular survivals by MTT assay. Comet assay, γ-H2AX focus formation assay and Western-blot were performed to investigate whether the observed cytotoxicity was associates with DNA damages. Finally, a xenograft tumor model was established in nude mice with C6 cells to analyze in vivo tumor inhibition effects of β-elemene, which was followed by determination of the expression of anti-apoptotic protein Bcl-2 via immunohistochemistry staining. Results showed that β-elemene could significantly inhibit the growth of glioma cells in a dose- and time-dependent manner. The combination of methoxyamine with β-elemene could result in a greater extent of DNA injuries in vitro. Furthermore, in vivo tumors exhibited a marked shrinkage in volume in β-elemene + methoxyamine treatment group. Immunohistochemistry analysis of the tumor tissues showed a distinctive decrease in Bcl-2 staining in β-elemene (56 %) and β-elemene + methoxyamine (36 %) groups when compared with the negative control (77 %). In conclusion, β-elemene exhibits a significant cytotoxic effect against glioma cells both in vitro and in vivo, which is likely to be mediated by its potential to damage tumor cell DNA and activate apoptotic pathway. Such growth inhibition effect of β-elemene could be potentiated by methoxyamine co-administration. Therefore, a combination of the two agents as a novel chemotherapeutic option for glioma merits further investigations.

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Acknowledgments

We would like to thank Dr. Yi-duo Hu from the Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Genetics, Harvard Medical School for his kind help in preparing this manuscript. We also would like to thank associate professor Xiu-yang Li, from the Department of Public Health, Zhejiang University School of Medicine, for her expertise in statistical analysis.

Conflict of interest

The authors have declared that no conflict of interest exist.

Funding

This study is supported in part by grant from the Zhejiang Provincial Administration of Traditional Chinese Medicine (Grant 2007CA060 and 2009CA044) and Zhejiang Provincial Natural Science Foundation (No. Y2091211).

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Authors and Affiliations

  1. Department of Neurosurgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China

    Yongjian Zhu, Hong Shen, Weiguo Liu & Jianmin Zhang

  2. Department of Pharmacology, Zhejiang Medical College, Hangzhou, Zhejiang, China

    Jue Hu

  3. Department of Neurosurgery, Huashan Hospital Affiliated to Fudan University, Shanghai, China

    Fang Shen

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  1. Yongjian Zhu
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  4. Hong Shen
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Correspondence to Jianmin Zhang.

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Zhu, Y., Hu, J., Shen, F. et al. The cytotoxic effect of β-elemene against malignant glioma is enhanced by base-excision repair inhibitor methoxyamine. J Neurooncol 113, 375–384 (2013). https://doi.org/10.1007/s11060-013-1136-0

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  • DOI: https://doi.org/10.1007/s11060-013-1136-0

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