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.
Laboratory of Pharmacology, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Korea.
Eun-Hee
EH
Lee
Yun-Kyung
YK
Lee
Young-Jin
YJ
Im
Jae-Ho
JH
Kim
Fumikazu
F
Okajima
Dong-Soon
DS
Im
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006863:Hydrogen-Ion Concentration; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013997:Time Factors; D020298:U937 Cells
D000970:Antineoplastic Agents; C061800:N,N-dimethylsphingosine; D013110:Sphingosine; C005682:safingol; D002118:Calcium