TY  - JOUR
A1  - Cardani, Diego
A1  - Sardi, Claudia
A1  - La Ferla, Barbara
A1  - D'Orazio, Guiseppe
A1  - Sommariva, Michele
A1  - Marcucci, Fabrizio
A1  - Olivero, Daniela
A1  - Tagliabue, Elda
A1  - Koepsell, Hermann
A1  - Nicotra, Francesco
A1  - Balsari, Andrea
A1  - Rumio, Christiano
T1  - Sodium glucose cotransporter 1 ligand BLF501 as a novel tool for management of gastrointestinal mucositis
JF  - Molecular Cancer
N2  - 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 X-2 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.
KW  - apoptosis
KW  - prevention
KW  - doxorubicin
KW  - cancer
KW  - gastrointestinal mucositis
KW  - SGLT-1
KW  - synthetic D-glucose analogy
KW  - chemotherapy
KW  - inflammation
KW  - clinical practice guidelines
KW  - intestinal mucositis
KW  - epithelial cells
KW  - oral mucositis
KW  - gene-expression
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-117352
SN  - 1476-4598
VL  - 13
IS  - 23
ER  -