Lactoferrin reduces methotrexate-induced small intestinal damage, possibly through inhibition of GLP-2-mediated epithelial cell proliferation.
A strategy protecting the small intestine against deleterious side effects associated with anti-cancer therapy is arresting epithelial cell cycling temporally. Since endogenous glucagon-like peptide-2 (GLP-2) is a trophic factor specific for intestinal epithelia, the possibility of inhibiting GLP-2-mediated cell proliferation by lactoferrin, thereby protecting the small intestine against deleterious side effects of anticancer therapy, was investigated. In Caco-2 cells, GLP-2-mediated proliferation was reduced in a dose-dependent manner using lactoferrin. Furthermore, in a rat model for methotrexate-induced mucositis, lactoferrin reduced BrdU incorporation in small intestinal epithelial cells, indicating inhibition of epithelial cell proliferation in vivo. Subsequently, protection against methotrexate-induced intestinal damage was found in corresponding regions. These results show, for the first time, that lactoferrin interferes with GLP-2-induced intestinal epithelial proliferation. It may therefore be hypothesized that lactoferrin protects the intestine against anticancer therapy-induced intestinal damage, via inhibition of GLP-2-induced small intestinal epithelial cell proliferation.
van't Land
Belinda
B
Department of Condition and Disease Specific Research, Numico-Research, PO Box 7005, 6700 CA Wageningen, Wageningen, The Netherlands.
van Beek
Noortje M A
NM
van den Berg
Jeroen J M
JJ
M'Rabet
Laura
L
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects*; D001973:Bromodeoxyuridine / Q000378:metabolism; D018938:Caco-2 Cells; D002455:Cell Division; D002478:Cells, Cultured; D019610:Cytoprotection / Q000502:physiology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000502:physiology; D005260:Female; D053767:Glucagon-Like Peptide 2; D004763:Glucagon-Like Peptides; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects*; D007781:Lactoferrin / Q000494:pharmacology*; D008727:Methotrexate / Q000009:adverse effects*; D010455:Peptides / Q000502:physiology*; D016133:Polymerase Chain Reaction; D051381:Rats; D011919:Rats, Inbred Strains
D000964:Antimetabolites, Antineoplastic; D053767:Glucagon-Like Peptide 2; D010455:Peptides; D004763:Glucagon-Like Peptides; D007781:Lactoferrin; D001973:Bromodeoxyuridine; D008727:Methotrexate