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

Please always quote using this URN: urn:nbn:de:bvb:20-opus-117352
  • 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 syntheticBackground: 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.show moreshow less

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Metadaten
Author: Diego Cardani, Claudia Sardi, Barbara La Ferla, Guiseppe D'Orazio, Michele Sommariva, Fabrizio Marcucci, Daniela Olivero, Elda Tagliabue, Hermann Koepsell, Francesco Nicotra, Andrea Balsari, Christiano Rumio
URN:urn:nbn:de:bvb:20-opus-117352
Document Type:Journal article
Faculties:Fakultät für Biologie / Julius-von-Sachs-Institut für Biowissenschaften
Language:English
Parent Title (English):Molecular Cancer
ISSN:1476-4598
Year of Completion:2014
Volume:13
Issue:23
Source:Molecular Cancer 2014 13:23. doi:10.1186/1476-4598-13-23
DOI:https://doi.org/10.1186/1476-4598-13-23
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=24495286
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
Tag:SGLT-1; apoptosis; cancer; chemotherapy; clinical practice guidelines; doxorubicin; epithelial cells; gastrointestinal mucositis; gene-expression; inflammation; intestinal mucositis; oral mucositis; prevention; synthetic D-glucose analogy
Release Date:2015/08/18
Licence (German):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung