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Open AccessArticle

Augmentation of Saporin-Based Immunotoxins for Human Leukaemia and Lymphoma Cells by Triterpenoid Saponins: The Modifying Effects of Small Molecule Pharmacological Agents

1
The Simon Flavell Leukaemia Research Laboratory, Southampton General Hospital, Southampton SO16 6YD, UK
2
Biomedical Imaging Unit, University of Southampton School of Medicine, Southampton General Hospital, Southampton SO16 6YD, UK
*
Authors to whom correspondence should be addressed.
Toxins 2019, 11(2), 127; https://doi.org/10.3390/toxins11020127
Received: 14 January 2019 / Revised: 11 February 2019 / Accepted: 14 February 2019 / Published: 20 February 2019
(This article belongs to the Collection Toxic and Pharmacological Effect of Plant Toxins)
Triterpenoid saponins from Saponinum album (SA) significantly augment the cytotoxicity of saporin-based immunotoxins but the mechanism of augmentation is not fully understood. We investigated the effects of six small molecule pharmacological agents, which interfere with endocytic and other processes, on SA-mediated augmentation of saporin and saporin-based immunotoxins (ITs) directed against CD7, CD19, CD22 and CD38 on human lymphoma and leukaemia cell lines. Inhibition of clathrin-mediated endocytosis or endosomal acidification abolished the SA augmentation of saporin and of all four immunotoxins tested but the cytotoxicity of each IT or saporin alone was largely unaffected. The data support the hypothesis that endocytic processes are involved in the augmentative action of SA for saporin ITs targeted against a range of antigens expressed by leukaemia and lymphoma cells. In addition, the reactive oxygen species (ROS) scavenger tiron reduced the cytotoxicity of BU12-SAP and OKT10-SAP but had no effect on 4KB128-SAP or saporin cytotoxicity. Tiron also had no effect on SA-mediated augmentation of the saporin-based ITs or unconjugated saporin. These results suggest that ROS are not involved in the augmentation of saporin ITs and that ROS induction is target antigen-dependent and not directly due to the cytotoxic action of the toxin moiety. View Full-Text
Keywords: saporin; immunotoxin; augmentation; saponin; endocytosis; reactive oxygen species saporin; immunotoxin; augmentation; saponin; endocytosis; reactive oxygen species
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Smith, W.S.; Johnston, D.A.; Holmes, S.E.; Wensley, H.J.; Flavell, S.U.; Flavell, D.J. Augmentation of Saporin-Based Immunotoxins for Human Leukaemia and Lymphoma Cells by Triterpenoid Saponins: The Modifying Effects of Small Molecule Pharmacological Agents. Toxins 2019, 11, 127.

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