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Shiga Toxin 1, as DNA Repair Inhibitor, Synergistically Potentiates the Activity of the Anticancer Drug, Mafosfamide, on Raji Cells
Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Via San Giacomo 14, Bologna 40126, Italy
Department of Biomolecular Sciences, University of Urbino "Carlo Bo",Via Saffi 2, Urbino 61029, Italy
Immunohematology and Transfusion Center, S. Orsola-Malpighi Hospital, Via Massarenti 9, Bologna 40138, Italy
Department of Clinical and Experimental Medicine, University of Parma, Via Volturno 39, Parma 43126, Italy
* Author to whom correspondence should be addressed.
Received: 17 January 2013; in revised form: 7 February 2013 / Accepted: 7 February 2013 / Published: 21 February 2013
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.
Keywords: Shiga toxin 1; Gb3Cer/CD77-expressing lymphomas; mafosfamide; DNA repair; autologous bone marrow transplantation
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Brigotti, M.; Arfilli, V.; Carnicelli, D.; Rocchi, L.; Calcabrini, C.; Ricci, F.; Pagliaro, P.; Tazzari, P.L.; Alfieri, R.R.; Petronini, P.G.; Sestili, P. Shiga Toxin 1, as DNA Repair Inhibitor, Synergistically Potentiates the Activity of the Anticancer Drug, Mafosfamide, on Raji Cells. Toxins 2013, 5, 431-444.
Brigotti M, Arfilli V, Carnicelli D, Rocchi L, Calcabrini C, Ricci F, Pagliaro P, Tazzari PL, Alfieri RR, Petronini PG, Sestili P. Shiga Toxin 1, as DNA Repair Inhibitor, Synergistically Potentiates the Activity of the Anticancer Drug, Mafosfamide, on Raji Cells. Toxins. 2013; 5(2):431-444.
Brigotti, Maurizio; Arfilli, Valentina; Carnicelli, Domenica; Rocchi, Laura; Calcabrini, Cinzia; Ricci, Francesca; Pagliaro, Pasqualepaolo; Tazzari, Pier L.; Alfieri, Roberta R.; Petronini, Pier G.; Sestili, Piero. 2013. "Shiga Toxin 1, as DNA Repair Inhibitor, Synergistically Potentiates the Activity of the Anticancer Drug, Mafosfamide, on Raji Cells." Toxins 5, no. 2: 431-444.