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Open Access Research

Sodium glucose cotransporter 1 ligand BLF501 as a novel tool for management of gastrointestinal mucositis

Diego Cardani1, Claudia Sardi12, Barbara La Ferla3, Giuseppe D’Orazio3, Michele Sommariva45, Fabrizio Marcucci6, Daniela Olivero7, Elda Tagliabue5, Hermann Koepsell8, Francesco Nicotra3, Andrea Balsari45 and Cristiano Rumio12*

Author Affiliations

1 Department of Pharmacology and Biomolecular Sciences, Università degli Studi di Milano, Via Trentacoste 2, 20133 Milan, Italy

2 Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano, Milan, Italy

3 Department of Biotechnology and Bioscience & CINMPIS, Università degli Studi di Milano-Bicocca, Piazza della Scienza 2, 20126 Milan, Italy

4 Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Via Mangiagalli 31, 20133 Milan, Italy

5 Istituto Nazionale per lo Studio e la Cura dei Tumori, Via Venezian, 1, 20133 Milano, Italy

6 Regina Elena National Cancer Institute, Via E. Chianesi 53, 00144 Rome, Italy

7 BiEssseA, Via A. D’Aosta 7, 20129 Milan, Italy

8 Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs-Institute, University of Würzburg, 97082 Würzburg, Germany

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Molecular Cancer 2014, 13:23  doi:10.1186/1476-4598-13-23

Published: 5 February 2014

Abstract

Background

Recent studies demonstrated that engagement of sodium glucose transporter 1 (SGLT-1) by orally administered D-glucose protects the intestinal mucosa from lipopolysaccharide (LPS)-induced injury. We tested whether SGLT-1 engagement might protect the intestinal mucosa from doxorubicin (DXR)- and 5-fluorouracil (5-FU)-induced injury in animal models mimicking acute or chronic mucositis.

Methods

Mice were treated intraperitoneally with DXR, alone or in combination with 5-FU, and orally with BLF501, a glucose-derived synthetic compound with high affinity for SGLT-1. Intestinal mucosal epithelium integrity was assessed by histological analysis, cellular proliferation assays, real-time PCR gene expression assays and Western blot assays. Student’s t-test (paired two-tailed) and χ2 analyses were used for comparisons between groups. Differences were considered significant at p < 0.05.

Results

BLF501 administration in mice treated with DXR and/or 5-FU decreased the injuries to the mucosa in terms of epithelial integrity and cellular proliferative ability. Co-treatment with BLF501 led to a normal expression and distribution of both zonula occludens-1 (ZO-1) and beta-catenin, which were underexpressed after treatment with either chemotherapeutic agent alone. BLF501 administration also restored normal expression of caspase-3 and ezrin/radixin/moesin (ERM), which were overexpressed after treatment with DXR and 5-FU. In SGLT1-/- mice, BLF501 had no detectable effects. BLF501 administration in wild-type mice with growing A431 tumors did not modify antitumor activity of DXR.

Conclusions

BLF501-induced protection of the intestinal mucosa is a promising novel therapeutic approach to reducing the severity of chemotherapy-induced mucositis.

Keywords:
Gastrointestinal mucositis; SGLT-1; Synthetic D-glucose analogs; Chemotherapy; Inflammation