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

BMC Gastroenterology

Research Article

Richard L Guerrant¹  Cirle A Warren¹  Snjezana Zaja-Milatovic¹  Herene Barros Miranda Lucena¹  Reinaldo B Oriá²  Renato André C Oliveira²  Orleâncio Gomes R Azevedo²  Aldo Ângelo M Lima²  Bruna Castro Oliveira²  Michael P Vitek³  Deysi Viviana T Wong⁴  Roberto César P Lima-Júnior⁴  Ronaldo A Ribeiro⁴  Tiê Bezerra Costa⁵  Celina Viana Araújo⁵ 

[1] Center for Global Health, School of Medicine, University of Virginia, Carter Harrison Bldg MR-6, 625 Crispell Drive, Room 2526, 22908, Charlottesville, VA, USA;Center for Global Health, School of Medicine, University of Virginia, Carter Harrison Bldg MR-6, 625 Crispell Drive, Room 2526, 22908, Charlottesville, VA, USA;Laboratoy of the Biology of Tissue Healing, Ontogeny and Nutrition, Institute of the Brazilian Semi-arid, School of Medicine, Federal University of Ceara, Rua Coronel Nunes de Melo, 1315 Rodolfo Teófilo, 60.430-270, Fortaleza, Ceará, Brazil;Cognosci Inc., Duke University, Research Triangle Park, Durham, NC, USA;Laboratory of Inflammation and Cancer, School of Medicine, Federal University of Ceara, Rua Coronel Nunes de Melo, 1315 Rodolfo Teófilo, 60.430-270, Fortaleza, Ceará, Brazil;Laboratoy of the Biology of Tissue Healing, Ontogeny and Nutrition, Institute of the Brazilian Semi-arid, School of Medicine, Federal University of Ceara, Rua Coronel Nunes de Melo, 1315 Rodolfo Teófilo, 60.430-270, Fortaleza, Ceará, Brazil;

关键词: Mucositis;    Apolipoprotein E;    5-fluorouracil;    Inflammation;    Cytokines;   

DOI  :  10.1186/1471-230X-12-35

 received in 2011-06-21, accepted in 2012-04-23,  发布年份 2012

来源: Springer

【 摘 要 】

BackgroundIntestinal 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.MethodsExperimental 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.ResultsVillus 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.ConclusionAltogether, these findings suggest that the novel ApoE COG 133 mimetic peptide can reduce 5-FU-induced intestinal changes and potentially benefit mucositis.

【 授权许可】

Unknown   
© Azevedo et al.; licensee BioMed Central Ltd. 2012. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.