Newly identified structurally disparate modulators of osmosensitive taurine efflux inhibit cell cycle progression

Abstract

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 μM): fluoxetine, ∼14; fluvoxamine, ∼24; amitriptyline, ∼32; imipramine, ∼32; mianserin, ∼40. A 48-h application of these compounds at these concentrations significantly increased arrest in the G0/1 stage of the cell cycle by ∼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.