Anti-inflammatory effects of indomethacin's methyl ester derivative and induction of apoptosis in HL-60 Cells.
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.
Chao
Su-Hui
SH
School of Pharmacy, College of Pharmacy, Taipei Medical University, Taiwan.
Wu
An-Bang
AB
Lee
Chia-Jung
CJ
Chen
Fu-An
FA
Wang
Ching-Chiung
CC
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects / Q000235:genetics; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005562:Formazans; D016193:G1 Phase / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D018922:HL-60 Cells; D006801:Humans; D007213:Indomethacin / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D007249:Inflammation / Q000188:drug therapy / Q000517:prevention & control*; D020128:Inhibitory Concentration 50; D015473:Leukemia, Promyelocytic, Acute / Q000473:pathology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008722:Methods; D051379:Mice; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D013778:Tetrazolium Salts
D000894:Anti-Inflammatory Agents, Non-Steroidal; D061945:Caspase Inhibitors; D005562:Formazans; D008070:Lipopolysaccharides; D013778:Tetrazolium Salts; C079782:MTT formazan; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D015232:Dinoprostone; D007213:Indomethacin