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Combination of levetiracetam and IFN-α increased temozolomide efficacy in MGMT-positive glioma

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Abstract

Purpose

Glioma, especially glioblastoma (GBM), is the most aggressive malignant brain tumor and its standard therapy is often ineffective because of temozolomide (TMZ) resistance. Reversal of the TMZ resistance might improve the prognosis of glioma patients. We previously found that interferon-α (IFN-α) and anti-epileptic drug levetiracetam (LEV) could sensitize glioma to TMZ, respectively. In this study, we further investigated the efficiency of combining of LEV and IFN-α for improving the efficacy of TMZ.

Methods

We evaluated whether LEV and IFN-α could increase TMZ efficacy using colony formation assay and cell viability assay with MGMT-positive and MGMT-negative glioma cell lines in vitro. Subcutaneous xenografts and orthotopic xenografts mice models were used in vivo to observe the tumor growth and mice survival upon treatments with TMZ, TMZ + IFN-α, TMZ + LEV, or TMZ + LEV + IFN-α. The expression levels of MGMT, markers of pro-apoptotic and anti-apoptotic in tumor samples were analyzed by Western blotting.

Results

The combinational use of IFN-α, LEV, and TMZ showed the best anti-tumor activity in MGMT-positive cell lines (U138, GSC-1, U118, and T98 G). TMZ + LEV + IFN-α further obviously increased TMZ + LEV or TMZ + IFN-α efficiency in MGMT-positive cell lines, while not in negative cell lines (SKMG-4, U87, U373, and U251) in vitro, which were also observed in subcutaneous mice models (U138, GSC-1 compared to SKMG-4, U87) and orthotopic models (GSC-1) in vivo. Strikingly, the combination of LEV and IFN-α together with TMZ significantly prolonged the survival of mice with orthotopic GSC-1 glioma. Furthermore, we confirmed that the combination of LEV and IFN-α enhanced the inhibition of MGMT and the activation of apoptosis in U138 tumor on the basis of TMZ treatment.

Conclusions

The combination use of LEV and IFN-α could be an optimal method to overcome TMZ resistance through obvious MGMT inhibition in MGMT-positive glioma.

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Code availability

Not applicable.

Availability of data and material

The datasets used and/or analyzed in the current study are available from the corresponding author on reasonable request.

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Funding

This study was supported by grants from the National Basic Research Program (973, 2015CB755505), the National Natural Science Foundation of China (NSFC) (81372685, 81872059, 81572479, and 81772677), Guangzhou Science Technology and Innovation Project (202002030114), the Science and Technology Planning Project (2016A020213004), and the Natural Science Foundation of Guangdong Province (NSFG) (2019A1515010702 and 2016A030313309).

Author information

Author notes

  1. Xiang-Rong Ni, Cheng-Cheng Guo, and Yan-Jiao Yu have contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery/Neuro-Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Rd East, Guangdong, 510060, People’s Republic of China

    Xiang-Rong Ni, Cheng-Cheng Guo, Yan-Jiao Yu, Zhi-Hui Yu, Hai-Ping Cai, Wei-Chi Wu, Jun-Xiao Ma, Fu-Rong Chen, Jing Wang & Zhong-Ping Chen

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  1. Xiang-Rong Ni
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Contributions

ZPC and JW conceived, wrote, and revised the article. XRN performed experiments, wrote, and edited the manuscript. CCG reviewed and edited the manuscript. YQ, HPC, ZHY, FRC, YJY, WCW, and JXM performed experiments and analyzed the data. All authors read and approved the final version of manuscript.

Corresponding authors

Correspondence to Jing Wang or Zhong-Ping Chen.

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The animal experiments were approved by the institutional ethics committee of Sun Yat-sen University Cancer Center.

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Ni, XR., Guo, CC., Yu, YJ. et al. Combination of levetiracetam and IFN-α increased temozolomide efficacy in MGMT-positive glioma. Cancer Chemother Pharmacol 86, 773–782 (2020). https://doi.org/10.1007/s00280-020-04169-y

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