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2002 Fiscal Year Final Research Report Summary

Investigation of molecular mechanisms of cell death induced by combination treatment with TRAIL and chemotherapy in malignant gliomas

Research Project

Project/Area Number 13671463
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Cerebral neurosurgery
Research InstitutionKyorin University

Principal Investigator

NAGANE Motoo  Kyorin University School of Medicine, Assistant Professor, 医学部, 講師 (60327468)

Co-Investigator(Kenkyū-buntansha) SAITO Isamu  Kyorin University School of Medicine, Professor, 医学部, 教授 (20186927)
Project Period (FY) 2001 – 2002
KeywordsTRAIL / DNA damage / Radiation therapy / Glioma / Apoptosis / DR5 / caspase / chemotherapy
Research Abstract

We investigated the molecular pathways involved in death signals induced by combination treatment with TRAIL and DNA damaging chemotherapeutic agents in glioma cells. FADD was expressed in glioma cells and expression of a dominat-negtive form of FADD significantly suppressed the synergistic cytotoxicity of the combination treatment. An initiator caspase, caspase-8, which forms DISC with death receptors, was cleaved and activated by the combination treatment. An essential effector caspase, caspase-3, was also cleaved and activated, resulting in cleavage of PARP, an intrinsic substrate of caspase-3, suggesting that cell death induced by the combination treatment is mediated by direct caspase activation pathways through FADD. Bid cleavage and release of cytochrome c and apoptosis-inducing factor (AIF) into cytoplasm upon the combination treatment were also observed, suggesting that the mitochondrial apoptosis pathways play an important role in its synergistic cytotoxiciy. Combination of T … More RAIL and X-ray radiotherapy (XRT) exhibited similar enhanced cytotoxicity in human glioma cells. XRT at 10 Gy upregulated DR5 expression and the cytotoxicity was abrogated in the presence of TRAIL neutralizing DR5-Fc, indicating that DR5 induction may be important in this effect. Similar to chemotherapy, XRT/TRAIL combination treatment activated FADD/caspase-8 mediated direct activation of caspase cascade and mitochondrial apoptosis pathways as well. U87MG cells which is wild type for p53 showed resistance to TRAIL/XRT therapy. Introduction of a dominant-negative p53, p53DD, did not sensitize U87MG cells to the combination treatment, suggesting that wild-type p53 function is not required for the enhanced cytotoxicity. TRAIL/XRT combination treatment did not affect viability of normal human astrocytes. Function of a transcription factor NF-kB was not involved in the synergistic cytotoxic effects of both TRAIL/chemotherapy and TRAIL/XRT combination in glioma cells. Our results suggest that TRAIL could be effectively combined with both DNA damaging chemotherapy and XRT, conventional therapeutic modalities of human malignant gliomas, and thus provide evidence that such combination treatment could be potential novel therapeutics against intractable malignant gliomas. Less

  • Research Products

    (10 results)

All Other

All Publications (10 results)

  • [Publications] Nagane M: "Human Glioblastoma xenografts overexpressing a tumor-specific mutant epidermal growth factor receptor sensitized to cisplatin by the AG1478 tyrosine kinase inhibitor"Journal of Neurosurgery. 95. 472-479 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nagane M: "Aberrant receptor signaling in human malignant gliomas : Mechanisms and therapeutic implications"Cancer Letters. 162 Suppl. S17-S21 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nagane N: "The potential of TRAIL for cancer chemotherapy"Apoptosis. 6. 191-197 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 永根 基雄: "薬剤耐性関連遺伝子の蛋白発現量によるグリオーマの個別化化学療法"ポストシークエンス時代における眼腫瘍の研究と治療 九州大学出版. 375-381 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 永根 基雄: "悪性神経膠腫に対するdeath receptor pathwayによる治療"Neuro-Oncology. 12. 33-42 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nagane,M., et al.: "Human glioblastoma xenografts overexpressing a tumor-specific mutant epidermal growth factor receptor sensitized to cisplatin by the AG1478 tyrosine kinase inhibitor"J Neurosurg. 95. 472-479 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nagane,M., et al.: "Aberrant receptor signaling in human malignant 2001, gliomas: Mechanisms and therapeutic implications"Cancer Lett 162 Suppl. 1. S17-S21 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nagane,M., et al.: "The Potential of TRAIL for Cancer Chemotherapy"Apoptosis. 6. 191-197 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nagane,M., et al.: "Treatment of malignant glioma by activation of death receptor pathways (in Japanese)"Neuro-Oncology. 12(1). 33-42 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nagene,M., et al., ed by, K.Tabuchi., and Shiraishi.: "Analysis of protein expression of chemoresistance in related genes for selection of anticancer drugs in T. human gliomas, (in Japanese), in Brain Tumor Research and Therapy the Postsequence Era"Kyushu-daigaku-shuppan. 375-382 (2002)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2004-04-14  

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