ABSTRACT
Cyclooxygenase-2 (COX-2) expression and peroxisome proliferator-activated receptor-gamma (PPARgamma) inactivation are linked to increased risk of human breast cancer. This study examines the effect of simultaneous targeting of COX-2 and PPARgamma on the proliferation of human breast cancer cells and on the expression of Bcl-2, BAX, and caspases-3 and -9, modulators of apoptotic cell death. Treatment of MDA-MB-231 breast cancer cells with NS-398 (a COX-2 inhibitor) or ciglitazone (CGZ, a PPARgamma-ligand) significantly inhibited cell proliferation and markedly increased apoptotic rates. These effects were accompanied by upregulation of BAX and caspases-3 and -9 mRNA expression and downregulation of Bcl-2. Compared to the influence of separate treatments, simultaneous treatment with NS-398 and CGZ synergistically inhibited cell proliferation and induced apoptotic cell death. In conclusion, combinational targeting of COX-2 and PPARgamma can inhibit the growth of human breast cancer cells and induce apoptosis to an extent more suprior to that produced by targeting each molecule alone. COX-2 and PPARgamma can be promising molecular targets for combinational chemoprevention or treatment of breast cancer.
Subject(s)
Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Isoenzymes/antagonists & inhibitors , Proto-Oncogene Proteins c-bcl-2 , Receptors, Cytoplasmic and Nuclear/metabolism , Transcription Factors/metabolism , Apoptosis/drug effects , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Caspase 3 , Caspases/genetics , Cell Cycle/drug effects , Cell Division/drug effects , Cell Line, Tumor , Cyclooxygenase 2 , Cyclooxygenase 2 Inhibitors , Cyclooxygenase Inhibitors/pharmacology , Female , Gene Expression/drug effects , Genes, bcl-2 , Humans , Membrane Proteins , Nitrobenzenes/pharmacology , Prostaglandin-Endoperoxide Synthases , Proto-Oncogene Proteins/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA, Neoplasm/genetics , RNA, Neoplasm/metabolism , Sulfonamides/pharmacology , Thiazolidinediones/pharmacology , bcl-2-Associated X ProteinABSTRACT
The present study examines the effect of tobacco smoking on the expression of cyclooxygenase (COX)-2 gene, COX enzymatic activity and prostaglandin (PG) synthesis in urothelial mucosal tissues from patients with bladder cancer and from normal individuals. The detection frequency of COX-2 mRNA was 2-fold higher in bladder cancer patients compared to controls and it was accompanied by a significantly increased COX enzymatic activity and PGE2 synthesis (p < 0.05). Smokers, in both control and patients groups, had higher COX-2 expression, COX activity, and PGE2 synthesis compared to the nonsmokers (p < 0.05). The number of cigarettes smoked in the cases, but not controls, correlated well with COX enzymatic activity (r = 0.42, p = 0.016). The observed over-expression of COX-2 gene in human urinary bladder and the concomitant increases in PG synthesis may explain, at least in part, the mechanism by which cigarette smoking influences the development of urothelial neoplasia.
