Saponins modulate the intracellular trafficking of protein toxins.
Type I ribosome inactivating proteins such as saporin from the plant Saponaria officinalis L. are widely used as toxin moieties of targeted anti-tumor toxins. For exerting cytotoxicity the toxin moieties have to be released into the cytosol of tumor cells. However the cytosolic transfer of toxin molecules into the cytosol is mostly an inefficient process. In this report we demonstrate that certain saponins, which are also biosynthesized by Saponaria officinalis L., specifically mediate the release of saporin out of the intracellular compartments into the cytosol without affecting the integrity of the plasma membrane. The relevant cellular compartments were identified as late endosomes and lysosomes. Further studies revealed that endosomal acidification is a prerequisite for the saponin-mediated release of saporin. Binding analysis demonstrated an association of the saponins with saporin in a pH-dependent manner. The applicability of the saponin-mediated effect was demonstrated in vivo in a syngeneic tumor model using a saporin-based targeted anti-tumor toxin in combination with characterized saponins.
Institut für Laboratoriumsmedizin, Klinische Chemie und Pathobiochemie, Charité - Universitätsmedizin Berlin, Germany. alexander.weng@charite.de
Alexander
A
Weng
Mayank
M
Thakur
Benedicta
B
von Mallinckrodt
Figen
F
Beceren-Braun
Roger
R
Gilabert-Oriol
Burkard
B
Wiesner
Jenny
J
Eichhorst
Stefan
S
Böttger
Matthias F
MF
Melzig
Hendrik
H
Fuchs
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D058948:Cell Tracking; D003600:Cytosol / Q000378:metabolism*; D004337:Drug Carriers / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity; D004705:Endocytosis; D004815:Epidermal Growth Factor / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D011485:Protein Binding; D021381:Protein Transport; D054789:Ribosome Inactivating Proteins, Type 1 / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity; D012503:Saponins / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity; D000076985:Saporins; D059010:Single-Cell Analysis; D020349:Surface Plasmon Resonance; D014018:Tissue Distribution; D023382:Toxicity Tests, Acute; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D054789:Ribosome Inactivating Proteins, Type 1; D012503:Saponins; D004815:Epidermal Growth Factor; D000076985:Saporins