Selectivity of Sphingosine-Induced Apoptosis

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 derivativeN,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.