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

BMC Gastroenterology

Reinaldo B Oriá²  Richard L Guerrant⁴  Michael P Vitek¹  Aldo Ângelo M Lima²  Cirle A Warren⁴  Ronaldo A Ribeiro³  Roberto César P Lima-Júnior³  Herene Barros Miranda Lucena⁴  Tiê Bezerra Costa²  Deysi Viviana T Wong³  Celina Viana Araújo²  Snjezana Zaja-Milatovic⁴  Bruna Castro Oliveira²  Renato André C Oliveira²  Orleâncio Gomes R Azevedo² 

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

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

Others  :  1113101
DOI  :  10.1186/1471-230X-12-35

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

【 摘 要 】

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.

【 授权许可】

   
2012 Azevedo et al.; licensee BioMed Central Ltd.

【 图 表 】

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