Recombinant mistletoe lectin induces p53-independent apoptosis in tumour cells and cooperates with ionising radiation.
Mistletoe extracts are used as alternative cancer treatment in addition to standard chemotherapy and radiation treatment and have an immunostimulatory and pain-relieving effect. A direct antitumour effect of mistletoe extracts against tumour cells of lymphoid origin has been linked to the D-galactoside-specific mistletoe lectin I. In this study, we investigated the cellular effect of bacterially expressed, recombinant mistletoe lectin alone or in combination with ionising radiation in a genetically defined p53-wild-type and p53-deficient E1A/ras-transformed murine tumour cells system. Downregulation of the proliferative activity and cell killing by recombinant mistletoe lectin occurred in a clear dose response (0.1-1 ng ml(-1)). Induction of apoptosis was p53-independent, but apoptosis-associated factor-1-dependent. Cellular treatment with lectin in combination with ionising radiation resulted in both p53-wild-type and p53-deficient tumour cells in an at least additive, antiproliferative effect and enhanced activation of caspase-3. Combined treatment with ionising radiation and lectin revealed a similar cytotoxic effect in human, p53-mutated adenocarcinoma cells. Thus, recombinant mistletoe lectin alone and in combination with ionising radiation bypasses often prevalent apoptotic deficiencies in treatment-resistant tumour cells.
Hostanska
K
K
Department of Internal Medicine, University Hospital Zurich, Raemistr. 100, Switzerland.
Vuong
V
V
Rocha
S
S
Soengas
M S
MS
Glanzmann
C
C
Saller
R
R
Bodis
S
S
Pruschy
M
M
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D053477:Apoptotic Protease-Activating Factor 1; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism; D011905:Genes, ras; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000528:radiation effects; D051379:Mice; D014784:Mistletoe / Q000737:chemistry; D008928:Mitochondria / Q000187:drug effects / Q000528:radiation effects; D009154:Mutation / Q000235:genetics; D037121:Plant Lectins / Q000494:pharmacology*; D028321:Plant Preparations / Q000494:pharmacology*; D010940:Plant Proteins; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011839:Radiation, Ionizing; D011994:Recombinant Proteins / Q000302:isolation & purification / Q000378:metabolism; D054790:Ribosome Inactivating Proteins, Type 2; D012680:Sensitivity and Specificity; D014118:Toxins, Biological / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
C506592:APAF1 protein, human; D017304:Annexin A5; C506593:Apaf1 protein, mouse; D053477:Apoptotic Protease-Activating Factor 1; D037121:Plant Lectins; D028321:Plant Preparations; D010940:Plant Proteins; D011506:Proteins; D011994:Recombinant Proteins; D054790:Ribosome Inactivating Proteins, Type 2; D014118:Toxins, Biological; D016159:Tumor Suppressor Protein p53; C009674:ribosome inactivating protein, Viscum; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases