Abstract
Indomethacin is used as an anti-inflammatory drug and a nonselective cyclooxygenase inhibitor. When indomethacin in methanol was photo-irradiated with an Hg lamp, methyl ester, ethyl ester, and gamma-lactone derivatives of indomethacin were produced. In the present study, we found that the methyl ester derivative of indomethacin (M-IN) could more potently inhibit prostaglandin E(2) (PGE(2)) and nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX 2) protein expression from lipopolysaccharide (LPS)-stimulated RAW 264.7 cells than indomethacin, similar to the effect of a non-steroidal anti-inflammatory drugs (NSAID). On the other hand, the results showed that M-IN with an IC(50) value maintained at 36.9 microg/ml for 12 h exhibited stronger cytotoxicity than ethyl ester, gamma-lactone derivatives of indomethacin, and indomethacin in promyelocytic leukemia HL-60 cells. Moreover, a series of biochemical analyses determined that M-IN caused apoptotic bodies, DNA fragmentation, and enhanced PARP and pro-caspase 3 degradation in HL-60 cells. These above results indicate that the photosynthesized product, M-IN, had stronger anti-inflammatory effects in LPS-stimulated RAW 264.7 cells and cytotoxicity effects in HL-60 cells than the parent drug, indomethacin.
MeSH terms
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / antagonists & inhibitors
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Anti-Inflammatory Agents, Non-Steroidal / therapeutic use*
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Apoptosis / drug effects*
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Apoptosis / genetics
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Caspase 3
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Caspase Inhibitors
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Caspases / metabolism
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Cell Survival / drug effects
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Cyclooxygenase 2 / drug effects
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Cyclooxygenase 2 / genetics
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Cyclooxygenase 2 / metabolism
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DNA Fragmentation / drug effects
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DNA Fragmentation / genetics
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Dinoprostone / antagonists & inhibitors
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Dinoprostone / genetics
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Dinoprostone / metabolism
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Dose-Response Relationship, Drug
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Formazans
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G1 Phase / drug effects
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Gene Expression / drug effects
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Gene Expression / genetics
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HL-60 Cells
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Humans
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Indomethacin / analogs & derivatives*
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Indomethacin / antagonists & inhibitors
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Indomethacin / therapeutic use*
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Inflammation / drug therapy
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Inflammation / prevention & control*
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Inhibitory Concentration 50
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Leukemia, Promyelocytic, Acute / pathology*
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Lipopolysaccharides / pharmacology
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Methods
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Mice
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Nitric Oxide Synthase Type II / antagonists & inhibitors
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Nitric Oxide Synthase Type II / drug effects
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Nitric Oxide Synthase Type II / genetics
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Nitric Oxide Synthase Type II / metabolism
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Poly(ADP-ribose) Polymerases / metabolism
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Tetrazolium Salts
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Caspase Inhibitors
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Formazans
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Lipopolysaccharides
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Tetrazolium Salts
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MTT formazan
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Nitric Oxide Synthase Type II
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Cyclooxygenase 2
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Poly(ADP-ribose) Polymerases
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CASP3 protein, human
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Casp3 protein, mouse
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Caspase 3
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Caspases
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Dinoprostone
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Indomethacin