Cross-Resistance of CD95- and Drug-Induced Apoptosis as a Consequence of Deficient Activation of Caspases (ICE/Ced-3 Proteases)

DOI PDF 被引用文献1件
  • Marek Los
    From Hematology/Oncology, University Children's Hospital, and the Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany; and the Institute of Biochemistry, University of Freiburg, Freiburg, Germany.
  • Ingrid Herr
    From Hematology/Oncology, University Children's Hospital, and the Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany; and the Institute of Biochemistry, University of Freiburg, Freiburg, Germany.
  • Claudia Friesen
    From Hematology/Oncology, University Children's Hospital, and the Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany; and the Institute of Biochemistry, University of Freiburg, Freiburg, Germany.
  • Simone Fulda
    From Hematology/Oncology, University Children's Hospital, and the Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany; and the Institute of Biochemistry, University of Freiburg, Freiburg, Germany.
  • Klaus Schulze-Osthoff
    From Hematology/Oncology, University Children's Hospital, and the Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany; and the Institute of Biochemistry, University of Freiburg, Freiburg, Germany.
  • Klaus-Michael Debatin
    From Hematology/Oncology, University Children's Hospital, and the Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany; and the Institute of Biochemistry, University of Freiburg, Freiburg, Germany.

書誌事項

公開日
1997-10-15
DOI
  • 10.1182/blood.v90.8.3118
公開者
American Society of Hematology

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説明

<jats:title>Abstract</jats:title> <jats:p>The cytotoxic effect of anticancer drugs has been shown to involve induction of apoptosis. We report here that tumor cells resistant to CD95 (APO-1/Fas) -mediated apoptosis were cross-resistant to apoptosis-induced by anticancer drugs. Apoptosis induced in tumor cells by cytarabine, doxorubicin, and methotrexate required the activation of ICE/Ced-3 proteases (caspases), similarly to the CD95 system. After drug treatment, a strong increase of caspase activity was found that preceded cell death. Drug-induced activation of caspases was also found in ex vivo-derived T-cell leukemia cells. Resistance to cell death was conferred by a peptide caspase inhibitor and CrmA, a poxvirus-derived serpin. The peptide inhibitor was effective even if added several hours after drug treatment, indicating a direct involvement of caspases in the execution and not in the trigger phase of drug action. Drug-induced apoptosis was also strongly inhibited by antisense approaches targeting caspase-1 and -3, indicating that several members of this protease family were involved. CD95-resistant cell lines that failed to activate caspases upon CD95 triggering were cross-resistant to drug-mediated apoptosis. Our data strongly support the concept that sensitivity for drug-induced cell death depends on intact apoptosis pathways leading to activation of caspases. The identification of defects in caspase activation may provide molecular targets to overcome drug resistance in tumor cells.</jats:p>

収録刊行物

  • Blood

    Blood 90 (8), 3118-3129, 1997-10-15

    American Society of Hematology

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