Dimethylsphingosine regulates intracellular pH and Ca(2+) in human monocytes

Dimethylsphingosine (DMS) was first reported as an inhibitor of protein kinase C and later has been used as a specific inhibitor of sphingosine kinase. Furthermore, its anti-cancer effect has become a basis for development of chemotherapy. Nevertheless, its anti-neoplastic mechanism has poorly been understood. In the present study, we observed that DMS increased intracellular pH and Ca(2+) concentration in U937 human monocytes. To further characterize these DMS-induced actions, we employed structurally-related sphingolipids and specific pharmacological tools such as inhibitors of protein kinase C and Na(+)/H(+) exchanger and found that the two responses of DMS were mimicked by four stereoisomers of sphingosine and two isomers to dihydrosphingosine, but not with sphingosine 1-phosphate, sphingosyl-phosphorylcholine, and C2-ceramide. Furthermore, DMS-induced pH increase was independent of Na(+)/H(+) exchanger activity. We also characterized the interrelationship between DMS-induced pH increase and DMS-induced Ca(2+) increase. Since DMS is considered to be a good anti-cancer candidate, our characterization of DMS actions provides useful information for development of DMS chemotherapy.