Sodium glucose cotransporter 1 ligand BLF501 as a novel tool for management of gastrointestinal mucositis
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
Molecular Cancer 2014, 13:23 doi:10.1186/1476-4598-13-23Published: 5 February 2014
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.
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.
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.
BLF501-induced protection of the intestinal mucosa is a promising novel therapeutic approach to reducing the severity of chemotherapy-induced mucositis.