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

Diego Cardani, Claudia Sardi, Barbara La Ferla, Giuseppe D'Orazio, Michele Sommariva, Fabrizio Marcucci, Daniela Olivero, Elda Tagliabue, Hermann Koepsell, Francesco Nicotra, Andrea Balsari, Cristiano Rumio

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number23
JournalMolecular Cancer
Volume13
Issue number1
DOIs
Publication statusPublished - Feb 5 2014

Keywords

  • Chemotherapy
  • Gastrointestinal mucositis
  • Inflammation
  • SGLT-1
  • Synthetic D-glucose analogs

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Medicine
  • Oncology

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