Shiga toxin 1, as DNA repair inhibitor, synergistically potentiates the activity of the anticancer drug, mafosfamide, on raji cells.

Abstract

Shiga toxin 1 (Stx1), produced by pathogenic Escherichia coli, targets a restricted subset of human cells, which possess the receptor globotriaosylceramide (Gb3Cer/CD77), causing hemolytic uremic syndrome. In spite of the high toxicity, Stx1 has been proposed in the treatment of Gb3Cer/CD77-expressing lymphoma. Here, we demonstrate in a Burkitt lymphoma cell model expressing this receptor, namely Raji cells, that Stx1, at quasi-non-toxic concentrations (0.05-0.1 pM), inhibits the repair of mafosfamide-induced DNA alkylating lesions, synergistically potentiating the cytotoxic activity of the anticancer drug. Conversely, human promyelocytic leukemia cells HL-60, which do not express Gb3Cer/CD77, were spared by the toxin as previously demonstrated for CD34+ human progenitor cells, and hence, in this cancer model, no additive nor synergistic effects were observed with the combined Stx1/mafosfamide treatment. Our findings suggest that Stx1 could be used to improve the mafosfamide-mediated purging of Gb3Cer/CD77+ tumor cells before autologous bone marrow transplantation.

• Authors: Maurizio Brigotti, Valentina Arfilli, Domenica Carnicelli, Laura Rocchi, Cinzia Calcabrini, Francesca Ricci, Pasqualepaolo Pagliaro, Pier Luigi Tazzari, Roberta R Alfieri, Pier Giorgio Petronini, Piero Sestili
• Journal: Toxins (Toxins (Basel)) Vol. 5 Issue 2 Pg. 431-44 (Feb 21 2013) ISSN: 2072-6651 [Electronic] Switzerland
• PMID: 23430607 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Protein Synthesis Inhibitors
• Shiga Toxin 1
• mafosfamide
• Cyclophosphamide

Topics

• Antineoplastic Agents (administration & dosage)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Cyclophosphamide (administration & dosage, analogs & derivatives)
• DNA Repair (drug effects)
• Drug Synergism
• HL-60 Cells
• Human Umbilical Vein Endothelial Cells
• Humans
• Protein Synthesis Inhibitors (administration & dosage)
• Shiga Toxin 1 (administration & dosage)