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

Abstract

BackgroundRecent 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.MethodsMice 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.ResultsBLF501 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.ConclusionsBLF501-induced protection of the intestinal mucosa is a promising novel therapeutic approach to reducing the severity of chemotherapy-induced mucositis.

Sex-dependent alteration of cardiac cytochrome P450 gene expression by doxorubicin in C57Bl/6 mice

“…These results corroborate the findings of a previous study where chronic DOX treatment caused a significant weight loss in both male and female Wistar rats, with 50% mortality only in male rats [12]. It is important to mention that the observed mortality in male mice can also be attributed to acute DOX-induced multi-organ toxicity including bone marrow toxicity, gastrointestinal toxicity, nephrotoxicity, and/or hepatotoxicity [38–40]. Determining sex-related differences of acute DOX-induced toxicity in these organs warrants further research.…”

Ketogal: A Derivative Ketorolac Molecule with Minor Ulcerogenic and Renal Toxicity

“…Therefore, the advantage of using a non-selective COX inhibitors with low toxicity still remains a goal of many preclinical researches. As previously reported, ketogal is not a simple prodrug, but it could be looked at as a new chemical entity ( Melisi et al, 2011 ; Cardani et al, 2014 ). Several manuscripts on NSAIDs prodrugs obtained blocking the free carboxylic group of NSAIDs only argue the gastrolesivity and neglect others crucial side effects ( Szabo, 2014 ; Suthar and Sharma, 2015 ).…”

Glucose transporters in the small intestine in health and disease

“…A dansyl C-glucoside (see called compound 5 in [220]) later on called BLF501 [53] was synthesized that is predicted to interact with Sglt1. BLF501 abolished the LPS-induced production of interleukin 8 (IL-8) in the human cell line HT29 similar to high D-glucose concentrations but was not effective when the expression of Sglt1 had been decreased by siRNA [220,292].…”

“…Complex pathophysiologic processes are involved that include damaging of epithelial and immune cells and affect their complex interactions [364]. Changes in proliferation, apoptosis, and/or necrosis of IECs and changes in their cytoskeleton architecture were associated with drug-induced mucositis in the small intestine [53,364]. Data obtained by two experimental setups suggest that SGLT1/Sglt1-mediated signaling influences effects of cytostatic drugs in the small intestine.…”