Inhibition of cell proliferation by potential peroxisome proliferator-activated receptor (PPAR) gamma agonists and antagonists.
This study was initiated to determine if potential PPAR gamma antagonists could block the inhibition of cell proliferation caused by 4-phenylbutyrate. The action of 4-phenylbutyrate differed from other PPAR gamma ligands examined in that it induces histone acetylation. Proliferation of DS19 mouse erythroleukemia cells was inhibited by PPAR gamma agonists (4-phenylbutyrate, rosiglitazone, ciglitazone and GW1929) and by potential PPAR gamma antagonists: BADGE (Biphenol A diglycidyl ether), GW9662, PD068235 and diclofenac. Combined incubations tended to exhibit additive inhibitory effects. Potential PPAR gamma agonists and antagonists inhibited the incorporation of thymidine into DNA of human prostate (PC3), colon (Caco-2) and breast (T47D) cancer cells but also affected NIH3T3 cells that have little or no expression of PPAR gamma. Lipid accumulation in T47D cells was seen after incubation with 4-phenylbutyrate and both potential PPAR gamma agonists and antagonists. The extent to which the effects of 4-phenylbutyrate on cell proliferation are mediated through PPAR gamma or induction of histone acetylation remains an open question. We conclude that potential PPAR gamma antagonists may fail to reverse the growth inhibitory effect of PPAR gamma ligands and may themselves act as growth inhibitory agents.
Lea
Michael A
MA
Department of Biochemistry and Molecular Biology, UMDNJ - New Jersey Medical School, Newark, New Jersey 07103, USA. lea@umdnj.edu
Sura
Monali
M
Desbordes
Charles
C
D000107:Acetylation / Q000187:drug effects; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004008:Diclofenac / Q000494:pharmacology; D006131:Growth Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D041681:NIH 3T3 Cells; D009574:Nitro Compounds / Q000494:pharmacology; D047495:PPAR gamma / Q000819:agonists* / Q000037:antagonists & inhibitors*; D010654:Phenylbutyrates / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D000077154:Rosiglitazone; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology
C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D006131:Growth Inhibitors; D006657:Histones; D009574:Nitro Compounds; C430895:PD 068235; D047495:PPAR gamma; D010654:Phenylbutyrates; D013844:Thiazoles; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D004008:Diclofenac; C075773:4-phenylbutyric acid