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Rutin increases the cytotoxicity of temozolomide in glioblastoma via autophagy inhibition

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Abstract

The chemotherapeutic agent temozolomide (TMZ) is widely used in the treatment of glioblastoma multiforme (GBM). Rutin, a citrus flavonoid ecglycoside found in edible plants, has neuroprotective and anticancer activities. This study aimed to investigate the efficacy and the underlying mechanisms of rutin used in combination with TMZ in GBM. In vitro cell viability assay demonstrated that rutin alone had generally low cytotoxic effect, but it enhanced the efficacy of TMZ in a dose-dependent manner. Subcutaneous and orthotopic xenograft studies also showed that tumor volumes were significantly lower in mice receiving combined TMZ/Rutin treatment as compared to TMZ or rutin alone treatment. Moreover, immunoblotting analysis showed that TMZ activated JNK activity to induce protective response autophagy, which was blocked by rutin, resulting in decreased autophagy and increased apoptosis, suggesting that rutin enhances TMZ efficacy both in vitro and in vivo via inhibiting JNK-mediated autophagy in GBM. The combination rutin with TMZ may be a potentially useful therapeutic approach for GBM patient.

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Funding

This study was supported by Health and Medical Research Fund (HMRF) founded by Hong Kong (Project No: 02132536).

Authors contributions

PZ performed the experiments, analyzed the data, wrote and revised the paper. SS designed the study and performed the experiments. NL, ASWH, KMYK, XZ and SYC performed the experiments and reviewed the paper. MWP, DL, YS, RY, JKSP reviewed the paper. GKKL designed the study and revised the paper. All authors read and approved the final manuscript.

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Authors and Affiliations

  1. Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, People’s Republic of China

    Pingde Zhang, Stella Sun, Ning Li, Amy Suk Wai Ho, Karrie Mei Yee Kiang, Xiaoqin Zhang, Yin Stephen Cheng, Ming Wai Poon, Derek Lee, Jenny Kan Suen Pu & Gilberto Ka Kit Leung

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  1. Pingde Zhang
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Correspondence to Gilberto Ka Kit Leung.

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Zhang, P., Sun, S., Li, N. et al. Rutin increases the cytotoxicity of temozolomide in glioblastoma via autophagy inhibition. J Neurooncol 132, 393–400 (2017). https://doi.org/10.1007/s11060-017-2387-y

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  • DOI: https://doi.org/10.1007/s11060-017-2387-y

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