E. Kishida et al., EVALUATION OF A TRANS CONFIGURATION FOR THE APOPTOSIS-INDUCING ACTIVITY OF CERAMIDE, Journal of lipid mediators and cell signalling, 16(3), 1997, pp. 127-137
The requirement of a trans double bond for the biological action of ce
ramide was assessed by comparing the apoptosis-inducing activity of va
rious ceramide analogs, The cis isomer and an acetylene type derivativ
e of sphingosine were chemically synthesized, and the 2-amino moiety w
as acylated with hexanoic acid, These cell-permeable ceramide derivati
ves were compared with N-hexanoyl sphingosine (C-6-Cer) or N-hexanoyl
dihydrosphingosine (C-6-DH-Cer) in their activity to induce apoptosis
of HL60. Either the cis isomer of C-6-Cer (C-6-cis-Cer) or a triple bo
nd derivative (C-6-TRP-Cer) induced apoptosis when assessed by fluores
cence microscopy of the morphological changes and electrophoretic anal
ysis of DNA C-6-TRP-Cer yielded the highest percentage of apoptotic ce
lls corresponding to three times that was induced by C-6-Cer. C-6-cis-
Cer also showed stronger activity than C-6-Cer. The minimum amounts of
C-6-TRP-Cer and C-6-cis derivative required to induce apoptosis were
0.1 and 0.5 mu M, respectively, while 1 mu M C-6-Cer was required to e
xhibit the activity. C-6-DH-Cer showed very low but significant activi
ty above 10 mu M. N- acetyl - sphingosine (C-2-Cer) induced more apopt
otic cells than C-6-Cer, and C-2-TRP-Cer wets much more potent than C-
2-Cer. These observations suggest that the trans configuration of cera
mide is not necessarily essential for the activity to induce apoptosis
. In addition, distinctive activity of C-6- or C-2-TRP-Cer suggests th
at this ceramide analog might be useful For developing a new type of a
ntitumor drug. (C) 1997 Elsevier Science B.V.