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.