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

Y. Shimazu, Kazuhiko Kurozumi, T. Ichikawa, Kentaro Fujii, M. Onishi, J. Ishida, T. Oka, Masami Watanabe, Yasutomo Nasu, H. Kumon, Isao Date

Research output: Contribution to journalArticle

17 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)146-154
Number of pages9
JournalGene Therapy
Volume22
Issue number2
DOIs
Publication statusPublished - Feb 7 2015

Fingerprint

Therapeutic Uses
Adenoviridae
Integrins
Glioma
Genetic Therapy
Cell Line
Therapeutics
Caspases
Reverse Transcription
Down-Regulation
Western Blotting
Apoptosis
Gene Expression
Polymerase Chain Reaction
Messenger RNA
Growth
Neoplasms
Proteins

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Medicine(all)

Cite this

Integrin antagonist augments the therapeutic effect of adenovirus-mediated REIC/Dkk-3 gene therapy for malignant glioma. / Shimazu, Y.; Kurozumi, Kazuhiko; Ichikawa, T.; Fujii, Kentaro; Onishi, M.; Ishida, J.; Oka, T.; Watanabe, Masami; Nasu, Yasutomo; Kumon, H.; Date, Isao.

In: Gene Therapy, Vol. 22, No. 2, 07.02.2015, p. 146-154.

Research output: Contribution to journalArticle

@article{eebf1bd4e5a445fcbd40d3573424fc3b,
title = "Integrin antagonist augments the therapeutic effect of adenovirus-mediated REIC/Dkk-3 gene therapy for malignant glioma",
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.",
author = "Y. Shimazu and Kazuhiko Kurozumi and T. Ichikawa and Kentaro Fujii and M. Onishi and J. Ishida and T. Oka and Masami Watanabe and Yasutomo Nasu and H. Kumon and Isao Date",
year = "2015",
month = "2",
day = "7",
doi = "10.1038/gt.2014.100",
language = "English",
volume = "22",
pages = "146--154",
journal = "Gene Therapy",
issn = "0969-7128",
publisher = "Nature Publishing Group",
number = "2",

}

TY - JOUR

T1 - Integrin antagonist augments the therapeutic effect of adenovirus-mediated REIC/Dkk-3 gene therapy for malignant glioma

AU - Shimazu, Y.

AU - Kurozumi, Kazuhiko

AU - Ichikawa, T.

AU - Fujii, Kentaro

AU - Onishi, M.

AU - Ishida, J.

AU - Oka, T.

AU - Watanabe, Masami

AU - Nasu, Yasutomo

AU - Kumon, H.

AU - Date, Isao

PY - 2015/2/7

Y1 - 2015/2/7

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84922402325&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84922402325&partnerID=8YFLogxK

U2 - 10.1038/gt.2014.100

DO - 10.1038/gt.2014.100

M3 - Article

VL - 22

SP - 146

EP - 154

JO - Gene Therapy

JF - Gene Therapy

SN - 0969-7128

IS - 2

ER -