Mistletoe lectin activates caspase-8/FLICE independently of death receptor signaling and enhances anticancer drug-induced apoptosis

Cancer Res. 1999 May 1;59(9):2083-90.

Abstract

Mistletoe lectin I (ML-I) is a major active component in plant extracts of Viscum album that is increasingly used in adjuvant cancer therapy. ML-I exerts potent immunomodulating and cytotoxic effects, although its mechanism of action is largely unknown. We show that treatment of leukemic T- and B-cell lines with ML-I induced apoptosis, which required the prior activation of proteases of the caspase family. The involvement of caspases is demonstrated because (a) a peptide caspase inhibitor almost completely prevented ML-I-induced cell death and (b) proteolytic activation of caspase-8, caspase-9, and caspase-3 was observed. Because caspase-8 has been implicated as a regulator of apoptosis mediated by death receptors, we further investigated a potential receptor involvement in ML-I-induced effects. Cell death triggered by ML-I was neither attenuated in cell clones resistant to CD95 nor in cells that were rendered refractory to other death receptors by overexpressing a dominant-negative FADD mutant. In contrast, ML-I triggered a receptor-independent mitochondria-controlled apoptotic pathway because it rapidly induced the release of cytochrome c into the cytosol. Because ML-I was also observed to enhance the cytotoxic effect of chemotherapeutic drugs, these data may provide a molecular basis for clinical trials using MLs in anticancer therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Chloromethyl Ketones / pharmacology
  • Antibiotics, Antineoplastic / pharmacology*
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apoptosis / drug effects*
  • Apoptotic Protease-Activating Factor 1
  • Arabidopsis Proteins*
  • Brefeldin A / pharmacology
  • Caspase 3
  • Caspase 8
  • Caspase 9
  • Caspases / metabolism*
  • Cysteine Proteinase Inhibitors / pharmacology
  • Cytochrome c Group / physiology
  • Drug Synergism
  • Enzyme Activation / drug effects
  • Enzyme Precursors / metabolism
  • Etoposide / pharmacology*
  • Fatty Acid Desaturases / genetics
  • Fatty Acid Desaturases / physiology*
  • Humans
  • Jurkat Cells / drug effects
  • Leukemia, B-Cell / metabolism
  • Leukemia, B-Cell / pathology*
  • Leukemia-Lymphoma, Adult T-Cell / metabolism
  • Leukemia-Lymphoma, Adult T-Cell / pathology*
  • Mitochondria / physiology
  • Mitomycin / pharmacology*
  • Neoplasm Proteins / metabolism*
  • Plant Preparations*
  • Plant Proteins / genetics
  • Plant Proteins / physiology*
  • Proteins / physiology
  • Ribosome Inactivating Proteins, Type 2
  • Toxins, Biological / pharmacology*
  • Tumor Cells, Cultured / drug effects
  • fas Receptor / physiology*

Substances

  • APAF1 protein, human
  • Amino Acid Chloromethyl Ketones
  • Antibiotics, Antineoplastic
  • Antineoplastic Agents, Phytogenic
  • Apoptotic Protease-Activating Factor 1
  • Arabidopsis Proteins
  • Cysteine Proteinase Inhibitors
  • Cytochrome c Group
  • Enzyme Precursors
  • Neoplasm Proteins
  • Plant Preparations
  • Plant Proteins
  • Proteins
  • Ribosome Inactivating Proteins, Type 2
  • Toxins, Biological
  • benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
  • fas Receptor
  • mistletoe lectin I
  • ribosome inactivating protein, Viscum
  • Brefeldin A
  • Mitomycin
  • Etoposide
  • Fatty Acid Desaturases
  • Fad7 protein, Arabidopsis
  • CASP3 protein, human
  • CASP8 protein, human
  • CASP9 protein, human
  • Caspase 3
  • Caspase 8
  • Caspase 9
  • Caspases