Influence of mistletoe lectins and cytokines induced by them on cell proliferation of human melanoma cells in vitro.

Although aqueous mistletoe extracts are widely used in complementary cancer therapy, the precise mode of action of their main therapeutic agents, the three mistletoe lectins (MLs), is poorly understood as they act both as cytotoxic agents and as immunomodulators due to their cytokine release by mononuclear cells. Thus, this study aims to investigate both the direct and the indirect effects of MLs on the growth of human melanoma cells in vitro. Proliferation of six human melanoma cell lines under ML treatment and additionally under the influence of cytokines induced by them (TNF-alpha, IL-1, IL-6) was assessed by means of the tetrazolium derived reduction (XTT) assay. Furthermore, ML binding patterns were analysed and correlated with the biological effects. All three MLs inhibited melanoma cell proliferation in a dose-dependent manner starting at very low ML concentrations (0.001-100 ng/ml) with ML-I being the most cytotoxic lectin (significant inhibition of ultra-sensitive cell line MV3 at 1 x 10(-13) ng ML-I/ml). Even if applied in a broad concentration range (0.0001-100 ng/ml) cytokines had no influence on cell proliferation at all. For ML-I, no association between binding intensity and cytotoxicity was observed, while for ML-II and -III an association between binding and toxicity was established. In conclusion, this study emphasises the direct anti-proliferative effect of the mistletoe lectins on melanoma cells with ML-I being superior to MLs-II and -III. The observation of an ultra-sensitivity of one cell line towards ML-I toxicity may serve as an explanation for the therapeutic success in anecdotal case reports and needs further investigations.