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.
Lee
Eun-Hee
EH
Laboratory of Pharmacology, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Korea.
Lee
Yun-Kyung
YK
Im
Young-Jin
YJ
Kim
Jae-Ho
JH
Okajima
Fumikazu
F
Im
Dong-Soon
DS
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