The Saponin-Mediated Enhanced Uptake of Targeted Saporin-Based Drugs is Strongly Dependent on the Saponin Structure

Abstract

Saponins are a group of plant glycosides consisting of a steroid or triterpenoid aglycone to which one or more sugar chains are attached. They exhibit cell membrane-permeabilizing properties and, thus, have been investigated for their therapeutic potential. Recently, at a non-permeabilizing concentration saponinum album from Gypsophila paniculata L. has been described to enhance the cytotoxicity of a chimeric toxin in a cell culture model. To elucidate whether this enhancing effect is also mediated by other saponins, we analyzed the ability of seven different saponins to enhance the cytotoxicity of a targeted chimeric toxin. The chimeric toxin is composed of saporin, a plant ribosome-inactivating toxin, a cleavable adapter, and human epidermal growth factor (EGF). Cytotoxicity on EGF receptor (EGFR)-bearing cells was analyzed both alone and after combined application of saponin and chimeric toxin. Only two of the tested saponins, quillajasaponin and saponinum album, enhanced cytotoxicity by more than 1,000-fold, whereas the enhancement factors of the other saponins were only approximately 10-fold. In contrast to saponinum album, quillajasaponin enhanced the cytotoxicity both on control cells lacking EGFR and on target cells, indicating that, in this case, the enhancement is not target cell receptor specific. This is also the case for some of the saponins with low enhancement factors. Saponinum album resulted in a more than 13,600-fold receptor-specific enhancement, decreasing the 50% inhibitory concentration (IC(50)) from 2.4 nM to 0.18 pM, which renders it the best option to promote saporin-3-based drug uptake while retaining specificity for the EGFR.

A lysine-free mutant of epidermal growth factor as targeting moiety of a targeted toxin

“…The TTs were used in final concentrations ranging from 0.3 to 100 nM on NIH-3T3 cells and 0.03 to 10 nM on HER14 cells. For experiments using Saponinum album (Spn), a saponin composite from Gypsophila paniculata L., as enhancer for the specific cytotoxicity of saporin-based TTs, the cells were preincubated for 5 min as described (Bachran et al 2006). In these experiments the TTs were used in final concentrations ranging from 0.03 to 10 nM on NIH-3T3 cells and 0.03 to 10 pM on HER14 cells.…”

Targeting antibodies to the cytoplasm

“…be enhanced by lysosomotropic agents like chloroquine 203 or by saponins that accumulate in endosomal membranes, 204,205 but interference with cellular processes may also lead to artifacts when these methods are used in cell physiological studies. Very recently, the PE translocation domain was successfully used in a tripartite construct.…”

Effect of resin from Commiphora swynnertonii on white blood cell and selected haematopoietic organs in albino mice (Mus musculus)

“…They are glycosides with distinctive foaming characteristics and are natural detergents found in certain plants (Ajali, 2004). Saponins consist of a sugar moiety usually containing glucose, galactose, glucoronic acid, xylose, rhamnose or methylpentose, glycosidically linked to a hydrophobic aglycone (sapogenin) which may be triterpenoid or steroid in nature (Bachram et al, 2006;Unakalamba et al, 2013). A study done by Akinnuga et al (2011) reported similar findings but for different plant species, Gongronema latifolium, that the presence of saponin in leaf extract of the plant significantly reduced all blood cells by suppressing the haematopoiesis system.…”