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Newly identified structurally disparate modulators of osmosensitive taurine efflux inhibit cell cycle progression
Mark J Belsey1, Steven J Culliford, Richard M Morley
1School of Medical Sciences, University of Bristol, University Walk, BS8 1TD Bristol, UK.
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 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.
Insights
Certain antidepressants and estrogen receptor modulators inhibit cell cycle progression by blocking the volume-sensitive organic osmolyte/anion channel, specifically impacting taurine efflux. This finding suggests a direct link between this channel
Area of Science:
- Molecular and Cellular Biology
- Pharmacology
- Biochemistry
Background:
- The volume-sensitive organic osmolyte/anion channel (VSOAC) plays a role in cellular homeostasis.
- Cell cycle progression is a fundamental biological process.
- Certain antidepressants and estrogen receptor modulators are known to affect cellular functions.
Purpose of the Study:
- To investigate the role of VSOAC activation in cell cycle progression.
- To determine if inhibition of VSOAC affects cell cycle progression.
- To identify specific compounds that inhibit VSOAC and impact cell cycle.
Main Methods:
- Utilized Fluorescence-Activated Cell Sorting (FACS) analysis for cell cycle assessment.
- Measured [14C]-taurine efflux to quantify VSOAC activity.
- Tested a panel of H1 antagonists, tricyclic antidepressants, and estrogen receptor modulators for cytotoxicity and VSOAC inhibition.
Main Results:
- Five compounds (fluoxetine, fluvoxamine, amitriptyline, imipramine, mianserin) specifically inhibited osmosensitive taurine efflux without cytotoxicity.
- These compounds demonstrated IC50 values in the micromolar range for taurine efflux inhibition.
- Application of these inhibitors led to a significant ~10% increase in G0/1 cell cycle arrest.
Conclusions:
- Inhibition of the volume-sensitive organic osmolyte/anion channel specifically blocks cell cycle progression.
- A strong correlation exists between osmosensitive taurine efflux and cell cycle progression.
- This study identifies key compounds that modulate VSOAC activity and cell cycle dynamics.