Abstract
We studied the mechanism by which the para and meta positional isomers of nitric oxide-donating aspirin (NO-ASA) inhibit human colon cancer cell growth. These compounds are promising chemopreventive agents and represent a broader class of novel drugs. The two isomers differ drastically in their 24-h IC50s for cell growth, which are 12 microM for p-NO-ASA and 230 microM for m-NO-ASA. We examined their effects on cell signaling cascades, including predominantly the mitogen activated protein kinases (MAPKs). The principal differences between the two isomers were: a) p-NO-ASA exerts its effect earlier than m-NO-ASA; b) the predominant effect of m-NO-ASA is on ERK1/2 and Akt; whereas that of p-NO-ASA is on JNK1/2, while both activate p38, with p-NO-ASA showing a stronger and earlier effect; c) ATF-2 is more responsive to m-NO-ASA and c-Jun to p-NO-ASA; d) both isomers seem to have similar effects on AP-1 binding, the main difference between them being the timing of the effect; p-NO-ASA's effect is early and m-NO-ASA's is late; e) p-NO-ASA has an earlier and stronger effect on p21, while m-NO-ASA's effect occurs later and is weaker; and f) cell cycle changes follow the effect on p21 expression. Our findings underscore the role of positional isomerism in modulating the pharmacological effects of drugs and have potentially important implications for the further development of these chemoprevention agents.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
MeSH terms
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Activating Transcription Factor 2 / metabolism
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Antineoplastic Agents / chemistry
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Antineoplastic 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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Cell Cycle / drug effects
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Cell Proliferation / drug effects*
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Colonic Neoplasms / genetics
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Colonic Neoplasms / metabolism*
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Colonic Neoplasms / pathology
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Cyclin D1 / metabolism
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism
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Dose-Response Relationship, Drug
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Enzyme Activation
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HT29 Cells
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Humans
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Inhibitory Concentration 50
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Isomerism
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / metabolism
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Mitogen-Activated Protein Kinase 8 / metabolism
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Mitogen-Activated Protein Kinase 9 / metabolism
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Nitric Oxide Donors / chemistry
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Nitric Oxide Donors / pharmacology*
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Phosphorylation
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Proto-Oncogene Proteins c-akt / metabolism
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Proto-Oncogene Proteins c-jun / metabolism
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RNA Interference
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Signal Transduction / drug effects*
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Signal Transduction / genetics
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Structure-Activity Relationship
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Time Factors
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Transcription Factor AP-1 / metabolism
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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ATF2 protein, human
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Activating Transcription Factor 2
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Antineoplastic Agents
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CCND1 protein, human
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CDKN1A protein, human
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Cyclin-Dependent Kinase Inhibitor p21
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Nitric Oxide Donors
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Proto-Oncogene Proteins c-jun
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Transcription Factor AP-1
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Cyclin D1
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Mitogen-Activated Protein Kinase 9
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinase 8
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p38 Mitogen-Activated Protein Kinases
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nitroaspirin
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Aspirin