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

Mol Cancer. 2014 Feb 5:13:23. doi: 10.1186/1476-4598-13-23.

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.

MeSH terms

  • Animals
  • Antineoplastic Agents / toxicity*
  • Blotting, Western
  • Cell Line, Tumor
  • Disease Models, Animal
  • Doxorubicin / toxicity
  • Female
  • Fluorescent Antibody Technique
  • Fluorouracil / toxicity
  • Gastrointestinal Diseases / chemically induced*
  • Gastrointestinal Diseases / pathology
  • Gastrointestinal Diseases / prevention & control
  • Glucose / analogs & derivatives*
  • Glucose / pharmacology
  • Heterografts
  • Humans
  • Immunohistochemistry
  • Ligands
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Mice, Nude
  • Mucositis / chemically induced*
  • Mucositis / pathology
  • Mucositis / prevention & control
  • Real-Time Polymerase Chain Reaction
  • Sodium-Glucose Transporter 1 / agonists*
  • Transcriptome / drug effects

Substances

  • Antineoplastic Agents
  • Ligands
  • Sodium-Glucose Transporter 1
  • Doxorubicin
  • Glucose
  • Fluorouracil