Novel anti-inflammatory action of edelfosine lacking toxicity with protective effect in experimental colitis.
Edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine; ET-18-OCH(3)) is an antitumor alkyl-lysophospholipid analog that binds lipid rafts, altering their protein composition (J Exp Med 200:353-365). Because L-selectin locates in lipid rafts and plays a crucial role in the recruitment of leukocytes into inflamed tissues, we hypothesized that edelfosine might affect inflammation by modulating L-selectin and inflammatory cell migration. Here, we have found that edelfosine inhibited neutrophil-endothelium interaction through L-selectin shedding. Oral treatment of edelfosine diminished inflammation in two murine animal models. Edelfosine showed a higher antiinflammatory effect than the nonsteroidal anti-inflammatory drug (NSAID) indomethacin in the bentonite mouse-paw edema model. Using a rat model of experimental colitis, edelfosine oral administration ameliorated the clinical and histopathologic severity of the inflammatory colitis with a dramatic decrease in mucosal damage and neutrophil infiltration. Colon sections from edelfosine-treated rats showed a remarkable reduction in ulcer formation, edema, and inflammatory cell infiltration. Edelfosine enhanced lipopolysaccharide-induced expression of anti-inflammatory interleukin-10 in mouse macrophages. Edelfosine oral treatment in rats, at doses 8-fold higher than those displaying anti-inflammatory action, lacked toxicity. Edelfosine treatment showed no any significant cardiotoxicity, hepatotoxicity or renal toxicity. Unlike NSAIDs, edelfosine did not inhibit prostaglandin E(2) synthesis in gastrointestinal mucosal biopsies, and no histologic alteration in gastrointestinal tract was detected after drug treatment. Thus, edelfosine shows a potent in vitro and in vivo anti-inflammatory activity while sparing gastric mucosa. Our data identify edelfosine as a novel anti-inflammatory drug by abating neutrophil infiltration through L-selectin shedding and may provide a new therapeutic approach for inflammatory bowel disease free from toxicity.
Mollinedo
Faustino
F
Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas-Universidad de Salamanca, Salamanca, Spain. fmollin@usal.es
Gajate
Consuelo
C
Morales
Ana I
AI
del Canto-Jañez
Esther
E
Justies
Nicole
N
Collía
Francisco
F
Rivas
Juan V
JV
Modolell
Manuel
M
Iglesias
Antonio
A
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D003093:Colitis, Ulcerative / Q000188:drug therapy*; D015232:Dinoprostone / Q000378:metabolism; D004487:Edema / Q000188:drug therapy; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D019041:L-Selectin / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D051379:Mice; D020556:Neutrophil Infiltration / Q000187:drug effects; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects; D010742:Phospholipid Ethers / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018675:Toxicity Tests
D000893:Anti-Inflammatory Agents; D010742:Phospholipid Ethers; D019041:L-Selectin; C026659:edelfosine; D015232:Dinoprostone