Abstract
There is current evidence implicating the Wnt/beta-catenin/TCF pathway in breast cancer. We investigated the effect of para- and meta-positional isomers of nitric oxide-releasing aspirin (NO-ASA), and aspirin (ASA) on MCF-7 human breast cancer cell growth and beta-catenin/TCF signaling. The p- and m-NO-ASA isomers strongly inhibited cell growth and beta-catenin/TCF transcriptional activity compared to ASA; the IC50s for growth inhibition were 57+/-4, 193+/-10 and >5000microM, and for transcriptional inhibition they were 12+/-1.8, 75+/-6.5 and >5000microM for p-, m-NO-ASA and ASA, respectively. p-NO-ASA reduced the expression of Wnt/beta-catenin downstream target gene cyclin D1, and total cellular beta-catenin levels. COX-2 expression was induced by p-NO-ASA, protein kinase C inhibitors reversed this induction. p-NO-ASA blocked the cell cycle transition at S to G2/M phase. These studies suggest a targeted chemopreventive/chemotherapeutic potential for NO-ASA against breast cancer.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Anticarcinogenic Agents / chemistry
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Anticarcinogenic Agents / pharmacology*
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Aspirin / analogs & derivatives*
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Aspirin / chemistry
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Aspirin / pharmacology
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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Breast Neoplasms / enzymology
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Breast Neoplasms / prevention & control*
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Cell Cycle / drug effects
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Cell Line, Tumor
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Cell Proliferation / drug effects*
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Cyclin D1 / genetics
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Cyclooxygenase 2 / biosynthesis*
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DNA-Binding Proteins / biosynthesis*
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DNA-Binding Proteins / genetics
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Down-Regulation
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Enzyme Induction
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Female
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Genes, Reporter
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Humans
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Inhibitory Concentration 50
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Isomerism
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Signal Transduction / drug effects
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Transcription Factor 4
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Transcription Factors / biosynthesis*
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Transcription Factors / genetics
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Transcription, Genetic / drug effects
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Wnt Proteins / biosynthesis*
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Wnt Proteins / genetics
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beta Catenin / biosynthesis*
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beta Catenin / genetics
Substances
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Anticarcinogenic Agents
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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CTNNB1 protein, human
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DNA-Binding Proteins
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TCF4 protein, human
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Transcription Factor 4
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Transcription Factors
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Wnt Proteins
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beta Catenin
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Cyclin D1
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Cyclooxygenase 2
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nitroaspirin
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Aspirin