Sodium glucose cotransporter 1 ligand BLF501 as a novel tool for management of gastrointestinal mucositis.
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.
Diego
D
Cardani
Claudia
C
Sardi
Barbara
B
La Ferla
Giuseppe
G
D'Orazio
Michele
M
Sommariva
Fabrizio
F
Marcucci
Daniela
D
Olivero
Elda
E
Tagliabue
Hermann
H
Koepsell
Francesco
F
Nicotra
Andrea
A
Balsari
Department of Pharmacology and Biomolecular Sciences, Università degli Studi di Milano, Via Trentacoste 2, 20133 Milan, Italy. cristiano.rumio@unimi.it.
Cristiano
C
Rumio
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000633:toxicity; D005260:Female; D005455:Fluorescent Antibody Technique; D005472:Fluorouracil / Q000633:toxicity; D005767:Gastrointestinal Diseases / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control; D005947:Glucose / Q000031:analogs & derivatives* / Q000494:pharmacology; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008819:Mice, Nude; D052016:Mucositis / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control; D060888:Real-Time Polymerase Chain Reaction; D051269:Sodium-Glucose Transporter 1 / Q000819:agonists*; D059467:Transcriptome / Q000187:drug effects
D000970:Antineoplastic Agents; D008024:Ligands; D051269:Sodium-Glucose Transporter 1; D004317:Doxorubicin; D005947:Glucose; D005472:Fluorouracil