Newly identified structurally disparate modulators of osmosensitive taurine efflux inhibit cell cycle progression.
FACS analysis and [14C]-taurine efflux were used to determine whether activation of the volume-sensitive organic osmolyte/anion channel plays a role in cell cycle progression. This was achieved by examining the effects of a collection of (i) H(1) antagonists and tricyclic antidepressants with a known inhibitory effect on cell cycle progression, and (ii) antidepressants and oestrogen receptor modulators with molecular structures likely to confer inhibition of the volume-sensitive organic osmolyte/anion channel. Of the 13 compounds examined in this study, the following showed no cytotoxicity following a 48-h exposure, and specifically inhibited osmosensitive taurine efflux (over lactate transport and anion exchange) with IC(50) values of (in microM): fluoxetine, approximately 14; fluvoxamine, approximately 24; amitriptyline, approximately 32; imipramine, approximately 32; mianserin, approximately 40. A 48-h application of these compounds at these concentrations significantly increased arrest in the G0/1 stage of the cell cycle by approximately 10%. The uniformity and specificity of the response elicited by these compounds strongly reinforces a correlation between cell cycle progression and osmosensitive taurine efflux activation.
Belsey
Mark J
MJ
School of Medical Sciences, University of Bristol, University Walk, BS8 1TD Bristol, UK.
Culliford
Steven J
SJ
Morley
Richard M
RM
Witchel
Harry J
HJ
Kozlowski
Roland Z
RZ
D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D006367:HeLa Cells; D006801:Humans; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013654:Taurine / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D014882:Water-Electrolyte Balance / Q000187:drug effects / Q000502:physiology*
D004364:Pharmaceutical Preparations; D013654:Taurine