Apolipoprotein E COG 133 mimetic peptide improves 5-fluorouracil-induced intestinal mucositis

• Published in: BMC gastroenterology Vol. 12; no. 1; p. 35
• Main Authors: Azevedo, Orleâncio Gomes R, Oliveira, Renato André C, Oliveira, Bruna Castro, Zaja-Milatovic, Snjezana, Araújo, Celina Viana, Wong, Deysi Viviana T, Costa, Tiê Bezerra, Lucena, Herene Barros Miranda, Lima, Jr, Roberto César P, Ribeiro, Ronaldo A, Warren, Cirle A, Lima, Aldo Ângelo M, Vitek, Michael P, Guerrant, Richard L, Oriá, Reinaldo B
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 13.07.2012; BioMed Central; BMC
• Subjects: 5-fluorouracil; Analysis; Animal experimentation; Animals; Apolipoprotein E; Apolipoproteins; Apolipoproteins E - genetics; Apolipoproteins E - pharmacology; Apolipoproteins E - therapeutic use; Apoptosis - drug effects; Biomimetic Materials - pharmacology; Biomimetic Materials - therapeutic use; Brain damage; Cancer; Cancer therapies; Cell death; Cell Movement - drug effects; Cell Proliferation - drug effects; Cell Survival - drug effects; Cells, Cultured; Chemotherapy; Cytokines; Cytokines - metabolism; Disease Models, Animal; Drug dosages; Fluorouracil; Fluorouracil - adverse effects; Gastroenterology; Glutamine; Health aspects; Immune system; In Vitro Techniques; Inflammation; Intestinal Diseases - chemically induced; Intestinal Diseases - drug therapy; Intestinal Diseases - pathology; Jejunum - drug effects; Jejunum - metabolism; Jejunum - pathology; Medical research; Medicine, Experimental; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular biology; Mucositis; Mucositis - chemically induced; Mucositis - drug therapy; Mucositis - pathology; Nitric oxide; Patient compliance; Peptide Fragments - pharmacology; Peptide Fragments - therapeutic use; Peptides; Peroxidase - metabolism; Physiological aspects; Proteins; Rats; Risk factors; Rodents; Studies; Brazil; United States
• ISSN: 1471-230X; 1471-230X
• DOI: 10.1186/1471-230X-12-35

Intestinal mucositis is one of the major troublesome side effects of anticancer chemotherapy leading to poor patient compliance. In this study we addressed the role of the novel apolipoprotein E (ApoE) COG 133 mimetic peptide in 5-fluorouracil (5-FU)-challenged Swiss mice and IEC-6 cell monolayers. Experiments were also conducted in C57BL6J ApoE knock-out mice to assess the effects of apoE peptide treatment. Experimental groups were as follows: unchallenged controls, 5-FU-challenged mice (450 mg/kg, i.p) with or without the ApoE peptide (0.3, 1, and 3 μM, given twice daily i.p. for 4 days). Mice were sacrificed 3 days after 5-FU challenge. Proximal small intestinal samples were harvested for molecular biology and histological processing. We conducted ELISA assays and RT-PCR to target IL-1β, TNF-α, IL-10, iNOS, and myeloperoxidase (MPO) to assess intestinal inflammation. Cell death and NF-κB assays were also conducted in apoE knock-out mice. In our in vitro models, IEC-6 cells were exposed to 1 mM of 5-FU in glutamine free media with or without the ApoE peptide (0.02, 0.2, 2, 5, 10, and 20 μM). We investigated IEC-6 cell proliferation and migration, 24 h after the 5-FU challenge. Additionally, apoptotic IEC-6 cells were measured by Tunel and flow cytometry. Equimolar doses of the ApoA-I (D4-F) peptide were also used in some experiments for comparative studies. Villus blunting and heavy inflammatory infiltrates were seen in the 5-FU-challenged group, findings that were partially ameliorated by the ApoE peptide. We found increased intestinal MPO and pro-inflammatory IL-1β and TNF-α levels, and TNF-α and iNOS transcripts, and reduction of IL-10 following 5-FU treatment, each of which were partially abrogated by the peptide. Improvements were also found in IEC-6 cell apoptosis and migration following ApoE and D-4F treatment. Altogether, these findings suggest that the novel ApoE COG 133 mimetic peptide can reduce 5-FU-induced intestinal changes and potentially benefit mucositis.