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.
MeSH terms
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Apoptosis / drug effects
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Breast Neoplasms / drug therapy
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism*
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Breast Neoplasms / pathology*
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Caspase 3
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Caspases / genetics
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Cell Cycle / drug effects
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Cell Division / drug effects
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Cell Line, Tumor
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Cyclooxygenase 2
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Cyclooxygenase 2 Inhibitors
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Cyclooxygenase Inhibitors / pharmacology
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Female
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Gene Expression / drug effects
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Genes, bcl-2
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Humans
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Isoenzymes / antagonists & inhibitors*
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Membrane Proteins
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Nitrobenzenes / pharmacology
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Prostaglandin-Endoperoxide Synthases
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins c-bcl-2*
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA, Neoplasm / genetics
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RNA, Neoplasm / metabolism
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Receptors, Cytoplasmic and Nuclear / metabolism*
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Sulfonamides / pharmacology
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Thiazolidinediones / pharmacology
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Transcription Factors / metabolism*
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bcl-2-Associated X Protein
Substances
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BAX protein, human
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Cyclooxygenase 2 Inhibitors
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Cyclooxygenase Inhibitors
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Isoenzymes
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Membrane Proteins
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Nitrobenzenes
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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RNA, Messenger
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RNA, Neoplasm
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Receptors, Cytoplasmic and Nuclear
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Sulfonamides
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Thiazolidinediones
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Transcription Factors
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bcl-2-Associated X Protein
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N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
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Cyclooxygenase 2
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PTGS2 protein, human
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Prostaglandin-Endoperoxide Synthases
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CASP3 protein, human
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Caspase 3
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Caspases
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ciglitazone