Effects of mistletoe (Viscum album L.) extracts Iscador on cell cycle and survival of tumor cells.
The molecular and cellular mechanisms by which mistletoe (Viscum album L.) extracts exert cytotoxic and immunomodulatory anti-tumoral effects are largely unknown. In this study the hypothesis that Iscador preparations induce tumor regression by cell cycle inhibition and/or interference with apoptotic signaling pathways in cancer cells was investigated. Also a possible effect on angiogenesis, which is a prerequisite for tumor growth in vivo, is studied in endothelial cell cultures. Furthermore, it was examined which apoptotic signaling route(s) is (are) activated by Iscador by studying specific pro-apoptotic proteins in cultured cells. To characterize these properties, 9 human cancer cell lines of different origin, one epidermis derived cell line and 2 endothelial cell cultures were incubated with different concentrations of Iscador Quercus Spezial and Iscador Malus Spezial. Cell cycle kinetic parameters were measured by bromodeoxyuridine (BrdU) pulse labeling and tubulin staining. Apoptotic responses were detected by M30 Cyto-Death or Annexin V/propidium iodide assays. Characterization of the apoptotic pathway(s) was performed by staining cells for amongst others active caspase 3 and cytochrome C (mitochondrial pathway), as well as active caspase 8 (death receptor pathway). The sensitivity to Iscador treatment varies strongly between different cell lines and also ing those derived from small cell lung cancer, and adenocarcinoma of the lung and breast, as well as endothelial cell cultures, Iscador caused early cell cycle inhibition followed by apoptosis in a dose dependent manner. Amongst the low responders are cell lines derived from colorectal carcinoma. In general Iscador Malus exerted a stronger response than Iscador Quercus. Apoptosis was induced by activating the mitochondrial but not the death receptor dependent pathway, at least in case of Iscador Quercus. Iscador Malus also seemed to induce apoptosis via the death receptor route, which may explain the higher sensitivity of cancer and endothelial cells to this preparation.
Harmsma
Marjan
M
MUbio Products B.V, Maastricht, The Netherlands.
Ummelen
Monique
M
Dignef
Wendy
W
Tusenius
Karel Jan
KJ
Ramaekers
Frans C S
FC
D017304:Annexin A5 / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001973:Bromodeoxyuridine; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004396:Coloring Agents; D004273:DNA, Neoplasm / Q000096:biosynthesis; D042783:Endothelial Cells / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008870:Microtubules / Q000187:drug effects / Q000648:ultrastructure; D010936:Plant Extracts / Q000494:pharmacology*; D010940:Plant Proteins / Q000494:pharmacology*; D011419:Propidium
D017304:Annexin A5; D000972:Antineoplastic Agents, Phytogenic; D004396:Coloring Agents; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D010936:Plant Extracts; D010940:Plant Proteins; D011419:Propidium; C077177:viscum album peptide; D001973:Bromodeoxyuridine