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

Published online

Journal Article

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: Altogether, these findings suggest that the novel ApoE COG 133 mimetic peptide can reduce 5-FU-induced intestinal changes and potentially benefit mucositis.

Full Text

Duke Authors

Cited Authors

  • Azevedo, OGR; Oliveira, RAC; Oliveira, BC; Zaja-Milatovic, S; Araújo, CV; Wong, DVT; Costa, TB; Lucena, HBM; Lima, RCP; Ribeiro, RA; Warren, CA; Lima, AÂM; Vitek, MP; Guerrant, RL; Oriá, RB

Published Date

  • July 13, 2012

Published In

Volume / Issue

  • 12 /

Start / End Page

  • 35 -

PubMed ID

  • 22524518

Pubmed Central ID

  • 22524518

Electronic International Standard Serial Number (EISSN)

  • 1471-230X

Digital Object Identifier (DOI)

  • 10.1186/1471-230X-12-35

Language

  • eng

Conference Location

  • England