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Integrin antagonist augments the therapeutic effect of adenovirus-mediated REIC/Dkk-3 gene therapy for malignant glioma

Gene Therapy volume 22, pages 146–154 (2015)Cite this article

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Abstract

Reduced expression in immortalized cells/Dickkopf-3 (REIC/Dkk-3) was identified as a gene whose expression is reduced in many human cancers. REIC/Dkk-3 expression is also downregulated in malignant glioma and regulates cell growth through caspase-dependent apoptosis. cRGD (EMD121974), an antagonist of integrins, has demonstrated preclinical efficacy against malignant glioma. In this study, we investigated the antiglioma effect of combination therapy using an adenovirus vector carrying REIC/Dkk-3 (Ad-REIC) and cRGD. Quantitative real-time reverse-transcription PCR revealed the reduction of REIC/Dkk-3 mRNA levels in malignant glioma cell lines. The reduction of REIC/Dkk-3 protein expression in malignant glioma cell lines was also confirmed with western blot analysis. After treatment with Ad-REIC and cRGD, the proliferative rate of malignant glioma cells was significantly reduced in a time-dependent manner. In vivo, there was a statistically significant increase in the survival of mice treated with Ad-REIC and cRGD combination therapy compared with Ad-REIC monotherapy. We identified an apoptotic effect following monotherapy with Ad-REIC. Moreover, cRGD augmented the antiglioma efficacy of Ad-REIC. These results may lead to a promising new approach for the treatment of malignant glioma.

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Acknowledgements

We thank M Arao and N Uemori for their technical assistance. This study was supported by grants-in-aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology to TI (Nos. 19591675 and 22591611) and KK (Nos. 20890133 and 21791364). A part of the present study was supported by the Grant in aids for strategic research promotion by Okayama University.

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Authors and Affiliations

  1. Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan,

    Y Shimazu, K Kurozumi, T Ichikawa, K Fujii, M Onishi, J Ishida, T Oka & I Date

  2. Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan,

    H Kumon

  3. Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama, Japan

    M Watanabe & Y Nasu

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  1. Y Shimazu
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Correspondence to K Kurozumi.

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Competing interests

Momotaro-Gene Inc. holds the patents of the Ad-REIC agent and develops the agent as a cancer therapeutic medicine. Dr Kumon, Dr Nasu and Dr Watanabe demonstrated the utility of the agent and also own the stock in Momotaro-Gene Inc. Okayama University and Momotaro-Gene Inc. are working together for the development of the Ad-REIC agent. Okayama University received the GMP-grade Ad-REIC agent from Momotaro-Gene Inc. to perform the clinical trials for the treatment of cancer patients. Okayama University also received research funds for the joint research. Dr Kumon is the Chief Science Officer in Momotaro-Gene Inc.

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Shimazu, Y., Kurozumi, K., Ichikawa, T. et al. Integrin antagonist augments the therapeutic effect of adenovirus-mediated REIC/Dkk-3 gene therapy for malignant glioma. Gene Ther 22, 146–154 (2015). https://doi.org/10.1038/gt.2014.100

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