Selectivity of sphingosine-induced apoptosis. Lack of activity of DL-erythyro-dihydrosphingosine.
Sphingosine (Sph) is emerging as an intracellular regulator of cellular differentiation and apoptosis (Ohta, et al., Cancer Res., 55, 691-697, 1995). We have recently found that both Sph and its methylated derivative N,N-dimethylsphingosine (DMS) inhibit mitogen-activated protein kinase (MAPK) activity, suggesting that Sph-induced apoptosis may be mediated at least partly through inhibition of MAPK (Sakakura, et al., Int J Oncol, 11, 31-39, 1997). We report in this study that three stereoisomers, D-erythro-Sph, L-threo-Sph, and DL-erythro-dihydrosphingosine, were tested in induction of apoptosis and inhibition of MAPK activity in three different kinds of solid tumor cell lines. D-erythro-Sph was strongest in these effects among three compounds. L-threo-Sphingosine was partly active. On the other hand, DL-erythro-dihydrosphingosine was totally inactive. These results demonstrate the specificity of sphingosine action in induction of apoptosis and inhibition of MAPK, suggesting that Sph may play an important role as a physiological intracellular messenger of apoptosis in these cancer cells.
Sakakura
C
C
First Department of Surgery, Kyoto Prefectural University of Medicine, Japan.
Sweeney
E A
EA
Shirahama
T
T
Hagiwara
A
A
Yamaguchi
T
T
Takahashi
T
T
Hakomori
S
S
Igarashi
Y
Y
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D053938:DNA Fragmentation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D009374:Neoplasms, Experimental / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D015290:Second Messenger Systems; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D013110:Sphingosine; C005682:safingol