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

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.

• Authors: 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
• Journal: Molecular cancer (Mol Cancer) Vol. 13 Pg. 23 (Feb 05 2014) ISSN: 1476-4598 [Electronic] England
• PMID: 24495286 (Publication Type: Journal Article)

Chemical References

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

Topics

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