The Intestinotrophic Peptide, GLP-2, Counteracts the Gastrointestinal Atrophy in Mice Induced by the Epidermal Growth Factor Receptor Inhibitor, Erlotinib, and Cisplatin

Abstract

The findings demonstrate that the intestinal mucosal damage induced by erlotinib alone and in combination with cisplatin can be counteracted by GLP-2 treatment, which might suggest a role for GLP-2 in the treatment of the gastrointestinal side-effects caused by these cancer therapeutics.

Determining the mechanisms of lapatinib-induced diarrhoea using a rat model

“…In addition, the number of crypt cells positive for the proliferative marker, Ki-67, was significantly higher in rats treated with combined paclitaxel/lapatinib. these findings were surprising given the previous research implicating mucosal atrophy with the use of small molecule egFr inhibitors [17][18][19]. In the combination treatment experiment, significant differences were only found in the groups co-treated with lapatinib and paclitaxel, indicating that lapatinib alone at 240 mg/kg does not have a substantial effect on epithelial proliferation.…”

“…the mechanisms of egFr tKI-induced diarrhoea have been hypothesised to be an increase in chloride secretion or direct mucosal damage [16]. In support of direct mucosal damage, a number of mouse studies have shown a reduction in intestinal morphometry following treatment with the egFr tKIs, elortinib [17], gefitinb [18] and canertinib [19], although further research is required to validate these findings. alternatively, egFr has been shown to play an important role in regulation of chloride secretion in the normal and inflamed colon [20], and so inhibition of this pathway may be an important mechanism in tKI-induced diarrhoea.…”

ErbB small molecule tyrosine kinase inhibitor (TKI) induced diarrhoea: Chloride secretion as a mechanistic hypothesis

“…One common hypothesis for the mechanism of action of diarrhoea following TKI treatment is thought to be due to inhibition of ErbB signalling within intestinal epithelia, leading to direct mucosal atrophy and damage [43][44][45]. Research suggested that this diarrhoea was associated with reduced growth, characterised by reduced growth and healing of the intestinal epithelium leading to mucosal atrophy due to the stimulatory effect of ErbB pathway on enterocyte proliferation [46], nutrient and electrolyte transport [47], brush border enzyme expression [48] and epithelial restitution being impeded [49].…”

Glucagon-like peptides 1 and 2

“…A large number of studies on the exogenous administration of GLP-2 to rodents have demonstrated its trophic effect on the small intestine [33][34][35][36][37][38][39][40][41][42][43] and colon [34,[39][40][41][42][43], but the exact underlying mechanism is poorly understood. Immunoneutralization of endogenous GLP-2 reduced the adaptive small intestine growth in diabetic rats, linking an increased plasma GLP-2 level to a proliferative response [44].…”

“…Rasmussen et al [43] found that the peptide reduced intestinal apoptosis and the decrease in villus height induced by chemotherapy. GLP-2 protected the intestinal mucosa from chemotherapy-induced injury in rats by preventing the reduction in villus height and the influx of MPOpositive cells in the ileum [3].…”