Apoptosis induction with 5-fluorocytosine/cytosine deaminase gene therapy for human malignant glioma cells mediated by adenovirus

Kazuhiko Kurozumi, Takashi Tamiya, Yasuhiro Ono, Shinji Otsuka, Hirokazu Kambara, Yoshiaki Adachi, Tomotsugu Ichikawa, Hirofumi Hamada, Takashi Ohmoto

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36 Citations (Scopus)

Abstract

Previously, we evaluated the therapeutic efficacy of the adenovirus-mediated transduction of the cytosine deaminase (CD) gene and 5-fluorocytosine (5-FC) for malignant gliomas. However, the molecular pathways that mediate the 5-FC/CD gene therapy-induced cell death remains to be elucidated. In this study, we examined the induction of apoptosis and the role of caspases in 5-FC/CD gene therapy using human malignant glioma cells [Gli36Δ5 (mutated p53) and U87MG (wild p53)]. The treatment with 5-FC/CD gene-therapy-induced apoptosis both in Gli36Δ5 cells and in U87MG cells according to flow cytometric analysis. Immunoblot analysis revealed that caspases 3 and 9 were processed in response to 5-FC/CD in a concentration- and time-dependent manner, but caspase 8 was not. Each caspase 3 and 9 inhibitor significantly reduced apoptosis triggered by 5-FC/CD, but the caspase 8 inhibitor did not affect apoptosis induction. 5-FC/CD significantly promoted the release of cytochorme c from mitochondria in a concentration-dependent manner. These results indicate that 5-FC/CD gene therapy induces apoptosis in human malignant glioma cells and that the apoptotic cell death is mediated by the activation of mitochondrial caspase cascades involving caspases 3 and 9. This is the first report concerning the apoptotic mechanism of 5-FC/CD gene therapy, and these findings could be used to increase the efficacy of suicide gene therapy systems for the treatment of malignant glioma.

Original languageEnglish
Pages (from-to)117-127
Number of pages11
JournalJournal of neuro-oncology
Volume66
Issue number1-2
DOIs
Publication statusPublished - Jan 2004

Keywords

  • 5-fluorocytosine
  • Adenovirus vector
  • Apoptosis
  • Caspase
  • Cytosine deaminase
  • Gene Therapy
  • Malignant gliomas
  • Mitochondria

ASJC Scopus subject areas

  • Oncology
  • Neurology
  • Clinical Neurology
  • Cancer Research

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    Kurozumi, K., Tamiya, T., Ono, Y., Otsuka, S., Kambara, H., Adachi, Y., Ichikawa, T., Hamada, H., & Ohmoto, T. (2004). Apoptosis induction with 5-fluorocytosine/cytosine deaminase gene therapy for human malignant glioma cells mediated by adenovirus. Journal of neuro-oncology, 66(1-2), 117-127. https://doi.org/10.1023/B:NEON.0000013494.98345.80