VIP-derived sequences modified by N-terminal stearyl moiety induce cell death: the human keratinocyte as a model.
Vasoactive intestinal peptide (VIP) is a recognized growth factor affecting many cell types. We have previously developed a series of lipophilic VIP analogues containing an N-terminal covalently attached stearyl moiety. The current studies identified stearyl-Nle(17)-VIP and stearyl-Nle(17)-neurotensin(6-11)VIP(7-28), acting at microM concentrations, as cytotoxic to human keratinocytes. The core C-terminal active VIP-derived peptide, stearyl-Lys-Lys-Tyr-Leu-NH(2) (St-KKYL-NH(2)), was identified as being responsible for the observed cytotoxicity. Cytotoxicity coincided with marked reduction in intracellular cyclic GMP and was abolished by co-treatment with the endonuclease inhibitor, aurine-tricarboxylic acid, suggesting apoptotic mechanisms. Stearyl-VIP derivatives thus offer lead compounds for future drug development against hyperproliferative skin conditions.
Granoth
R
R
Department of Clinical Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Israel.
Fridkin
M
M
Rubinraut
S
S
Gozes
I
I
D017209:Apoptosis / Q000187:drug effects; D001312:Aurintricarboxylic Acid / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects*; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000473:pathology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008858:Microscopy, Phase-Contrast; D014660:Vasoactive Intestinal Peptide / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology*
D004791:Enzyme Inhibitors; C086770:stearyl-norleucine(17)-vasoactive intestinal peptide; D014660:Vasoactive Intestinal Peptide; D001312:Aurintricarboxylic Acid; D007770:L-Lactate Dehydrogenase; D006152:Cyclic GMP