title: Combined application of saponin and chimeric toxins drastically enhances the targeted cytotoxicity on tumor cells.
abstract: Immunotoxins have to be administered in high doses due to low cytosolic uptake with the consequence of severe side effects. Recently we found that the cytotoxic activity from Agrostemma githago seeds can be attributed to a synergistic toxicity of a triterpenoid saponin and a ribosome-inactivating protein. Here we investigated whether saponins are able to enhance the efficacy of a receptor-specific chimeric toxin consisting of saporin-3, epidermal growth factor and a molecular adapter previously shown to reduce side effects on non-target cells. Pre-applied saponin enhances the target cell-specific cytotoxic effect, dependent on the cell line, between 3560- and 385,000-fold with an IC50 up to 0.67 pM. Non-target cells are not affected at the same concentration. At the optimal concentrations of the chimeric toxin and saponin application of either one of the components shows no cytotoxicity at all proving a synergistic effect. In the presence of saponin ligand-free saporin-3 does not exhibit any cytotoxic effect up to 0.1 nM providing further evidence for an increased specificity. This synergistic effect is in the same order of magnitude as in a mouse model. Our investigations clearly demonstrate that a combined administration of saponin and chimeric toxins opens up a promising perspective for tumor therapy.
authors.affiliation: Institut für Klinische Chemie und Pathobiochemie, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, D-12200 Berlin, Germany.
authors.forename: Iring
authors.initials: I
authors.lastname: Heisler
authors.forename: Mark
authors.initials: M
authors.lastname: Sutherland
authors.forename: Christopher
authors.initials: C
authors.lastname: Bachran
authors.forename: Philipp
authors.initials: P
authors.lastname: Hebestreit
authors.forename: Anna
authors.initials: A
authors.lastname: Schnitger
authors.forename: Matthias F
authors.initials: MF
authors.lastname: Melzig
authors.forename: Hendrik
authors.initials: H
authors.lastname: Fuchs
mesh_terms: D000818:Animals; D029748:Caryophyllaceae / Q000737:chemistry; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D004338:Drug Combinations; D004357:Drug Synergism; D006801:Humans; D000922:Immunotoxins / Q000494:pharmacology*; D051379:Mice; D041681:NIH 3T3 Cells; D010940:Plant Proteins / Q000494:pharmacology*; D012503:Saponins / Q000494:pharmacology*
chemical_list: D004338:Drug Combinations; D000922:Immunotoxins; D010940:Plant Proteins; D012503:Saponins