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We have been investigating the degree to which the inhibitory effects of phenyl alkanoic acids on cell proliferation are mediated by effects on histone acetylation or are mediated though activation of peroxisome proliferator-activated receptor (PPAR) gamma. The degree to which reported PPAR gamma antagonists interact with the effects of phenyl alkanoic acids was studied. Proliferation of DS19 mouse erythroleukemia cells was inhibited by PPAR gamma agonists (rosiglitazone, ciglitazone and GW1929) and by compounds reported to function as PPAR gamma antagonists in some systems: BADGE (Biphenol A diglycidyl ether), GW9662 and PD068235. Combined studies did not show antagonistic effects on growth and tended to exhibit additive inhibitory effects. The putative PPAR gamma antagonists also failed to reverse the growth inhibitory effects of the phenyl alkanoic acids, phenylbutyrate and 5-phenyl-2,4-pentadienoate (CG1255). Incubation with 10-20 μM GW9662 for 3 days caused inhibitory effects on the incorporation of tritium-labeled thymidine into DNA of human prostate (PC3), colon (Caco-2) and breast (T47D) cancer cells. Inhibitory effects were also seen after incubation with 30 μM PD068235. Preincubation for 24 hours with either 10 μM PD068235 or 10 μM GW9662 did not reverse the inhibitory effect of a 3 day incubation with 2 mM 4phenylbutyrate or 30 μM ciglitazone on the incorporation of thymidine in T47D cells. Lipid accumulation in T47D human breast cancer cells was used as a measure of differentiating activity, It was increased by the phenyl alkanoic acids studied with chain lengths between 4 and 10 carbons. Lipid accumulation was also seen after incubation with both PPAR gamma agonists and putative antagonists. GW9662 at 20μM and 30 μM PD068235 did not increase histone acetylation and 20 μM GW9662 did not affect the hyperacetylation induced in DS19 cells by 2 mM phenylbutyrate. In conclusion the extent to which effects of phenyl alkanoic acids on cell proliferation are mediated through PPAR gamma remains an open question, but we conclude that agents that serve as PPAR gamma antagonists in some systems may fail to reverse the growth inhibitory effect of PPAR gamma ligands and may themselves act as growth inhibitory agents.

[Proc Amer Assoc Cancer Res, Volume 45, 2004]