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Pharmazentrum Frankfurt, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt, 60590 Frankfurt am Main, Germany
1Correspondence: Pharmazentrum Frankfurt, Klinikum der Johann Wolfgang Goethe-Universität, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany. E-mail: geisslinger{at}em.uni-frankfurt.de
Several studies have demonstrated unequivocally that certain
nonsteroidal anti-inflammatory drugs (NSAIDs) such as sodium
salicylate, sulindac, ibuprofen, and flurbiprofen cause
anti-inflammatory and antiproliferative effects independent of
cyclooxygenase activity and prostaglandin synthesis inhibition. These
effects are mediated through inhibition of certain transcription
factors such as NF-
B and AP-1. The respective NSAIDs might interfere
directly with the transcription factors, but their effects are probably
mediated predominantly through alterations of the activity of cellular
kinases such as IKKß, Erk, p38 MAPK, or Cdks. These effects
apparently are not shared by all NSAIDs, since indomethacin failed to
inhibit NF-B and AP-1 activation as well as Erk and Cdk activity. In
contrast, indomethacin was able to activate PPAR
, which was not
affected by sodium salicylate or aspirin. The differences in
cyclooxygenase-independent mechanisms may have consequences for the
specific use of these drugs in individual patients because additional
effects may either enhance the efficacy or reduce the toxicity of the
respective compounds.—Tegeder, I., Pfeilschifter, J., Geisslinger, G.
Cyclooxygenase-independent actions of cyclooxygenase inhibitors
Key Words: aspirin • NSAIDs • apoptosis • metalloproteinase
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J. C. H. Hardwick, M. van Santen, G. R. van den Brink, S. J. H. van Deventer, and M. P. Peppelenbosch DNA array analysis of the effects of aspirin on colon cancer cells: involvement of Rac1 Carcinogenesis, July 1, 2004; 25(7): 1293 - 1298. [Abstract] [Full Text] [PDF]
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A. H. Schonthal, C. R. Herzog, M. V. Swamy, and C. V. Rao Correspondence re: M. V. Swamy et al., Inhibition of COX-2 in Colon Cancer Cell Lines by Celecoxib Increases the Nuclear Localization of Active p53. Cancer Res 2003;63:5239-42. Cancer Res., April 15, 2004; 64(8): 2937 - 2938. [Full Text] [PDF]
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N. Osakabe, A. Yasuda, M. Natsume, and T. Yoshikawa Rosmarinic acid inhibits epidermal inflammatory responses: anticarcinogenic effect of Perilla frutescens extract in the murine two-stage skin model Carcinogenesis, April 1, 2004; 25(4): 549 - 557. [Abstract] [Full Text] [PDF]
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 D. Ishiyama, D. Vujaklija, and J. Davies Novel Pathway of Salicylate Degradation by Streptomyces sp. Strain WA46 Appl. Envir. Microbiol., March 1, 2004; 70(3): 1297 - 1306. [Abstract] [Full Text] [PDF]
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A. L. Lovering, J. P. Ride, C. M. Bunce, J. C. Desmond, S. M. Cummings, and S. A. White Crystal Structures of Prostaglandin D2 11-Ketoreductase (AKR1C3) in Complex with the Nonsteroidal Anti-Inflammatory Drugs Flufenamic Acid and Indomethacin Cancer Res., March 1, 2004; 64(5): 1802 - 1810. [Abstract] [Full Text] [PDF]
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 D. Merkus, B. Houweling, A. Zarbanoui, and D. J. Duncker Interaction between prostanoids and nitric oxide in regulation of systemic, pulmonary, and coronary vascular tone in exercising swine Am J Physiol Heart Circ Physiol, March 1, 2004; 286(3): H1114 - H1123. [Abstract] [Full Text] [PDF]
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A. F. Badawi, M. B. Eldeen, Y. Liu, E. A. Ross, and M. Z. Badr Inhibition of Rat Mammary Gland Carcinogenesis by Simultaneous Targeting of Cyclooxygenase-2 and Peroxisome Proliferator-activated Receptor {gamma} Cancer Res., February 1, 2004; 64(3): 1181 - 1189. [Abstract] [Full Text] [PDF]
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D. Campa, S. Zienolddiny, V. Maggini, V. Skaug, A. Haugen, and F. Canzian Association of a common polymorphism in the cyclooxygenase 2 gene with risk of non-small cell lung cancer Carcinogenesis, February 1, 2004; 25(2): 229 - 235. [Abstract] [Full Text] [PDF]
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S. Weggen, J. L. Eriksen, S. A. Sagi, C. U. Pietrzik, V. Ozols, A. Fauq, Todd. E. Golde, and E. H. Koo Evidence That Nonsteroidal Anti-inflammatory Drugs Decrease Amyloid {beta}42 Production by Direct Modulation of {gamma}-Secretase Activity J. Biol. Chem., August 22, 2003; 278(34): 31831 - 31837. [Abstract] [Full Text] [PDF]
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Q. Yan, J. Zhang, H. Liu, S. Babu-Khan, R. Vassar, A. L. Biere, M. Citron, and G. Landreth Anti-Inflammatory Drug Therapy Alters {beta}-Amyloid Processing and Deposition in an Animal Model of Alzheimer's Disease J. Neurosci., August 20, 2003; 23(20): 7504 - 7509. [Abstract] [Full Text] [PDF]
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S. Weggen, J. L. Eriksen, S. A. Sagi, C. U. Pietrzik, Todd. E. Golde, and E. H. Koo A{beta}42-lowering Nonsteroidal Anti-inflammatory Drugs Preserve Intramembrane Cleavage of the Amyloid Precursor Protein (APP) and ErbB-4 Receptor and Signaling through the APP Intracellular Domain J. Biol. Chem., August 15, 2003; 278(33): 30748 - 30754. [Abstract] [Full Text] [PDF]
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 N. Grosser and H. Schroder Aspirin Protects Endothelial Cells From Oxidant Damage Via the Nitric Oxide-cGMP Pathway Arterioscler Thromb Vasc Biol, August 1, 2003; 23(8): 1345 - 1351. [Abstract] [Full Text] [PDF]
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F. G. Bottone Jr., J. M. Martinez, J. B. Collins, C. A. Afshari, and T. E. Eling Gene Modulation by the Cyclooxygenase Inhibitor, Sulindac Sulfide, in Human Colorectal Carcinoma Cells: POSSIBLE LINK TO APOPTOSIS J. Biol. Chem., July 3, 2003; 278(28): 25790 - 25801. [Abstract] [Full Text] [PDF]
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 S. A. Benitah, P. F. Valeron, and J. C. Lacal ROCK and Nuclear Factor-{kappa}B-dependent Activation of Cyclooxygenase-2 by Rho GTPases: Effects on Tumor Growth and Therapeutic Consequences Mol. Biol. Cell, July 1, 2003; 14(7): 3041 - 3054. [Abstract] [Full Text] [PDF]
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Y. Takahashi, I. Hayashi, Y. Tominari, K. Rikimaru, Y. Morohashi, T. Kan, H. Natsugari, T. Fukuyama, T. Tomita, and T. Iwatsubo Sulindac Sulfide Is a Noncompetitive gamma -Secretase Inhibitor That Preferentially Reduces Abeta 42 Generation J. Biol. Chem., May 9, 2003; 278(20): 18664 - 18670. [Abstract] [Full Text] [PDF]
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G. Hawcroft, S. H. Gardner, and M. A. Hull Activation of Peroxisome Proliferator-Activated Receptor gamma Does Not Explain the Antiproliferative Activity of the Nonsteroidal Anti-Inflammatory Drug Indomethacin on Human Colorectal Cancer Cells J. Pharmacol. Exp. Ther., May 1, 2003; 305(2): 632 - 637. [Abstract] [Full Text] [PDF]
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S. G. Wilson, C. D. Bryant, W. R. Lariviere, M. S. Olsen, B. E. Giles, E. J. Chesler, and J. S. Mogil The Heritability of Antinociception II: Pharmacogenetic Mediation of Three Over-the-Counter Analgesics in Mice J. Pharmacol. Exp. Ther., May 1, 2003; 305(2): 755 - 764. [Abstract] [Full Text] [PDF]
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J.-B. Yoon, S.-J. Kim, S.-G. Hwang, S. Chang, S.-S. Kang, and J.-S. Chun Non-steroidal Anti-inflammatory Drugs Inhibit Nitric Oxide-induced Apoptosis and Dedifferentiation of Articular Chondrocytes Independent of Cyclooxygenase Activity J. Biol. Chem., April 18, 2003; 278(17): 15319 - 15325. [Abstract] [Full Text] [PDF]
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 M. Maccarrone, N. Battista, M. Meloni, M. Bari, G. Galleri, P. Pippia, A. Cogoli, and A. Finazzi-Agro Creating conditions similar to those that occur during exposure of cells to microgravity induces apoptosis in human lymphocytes by 5-lipoxygenase-mediated mitochondrial uncoupling and cytochrome c release J. Leukoc. Biol., April 1, 2003; 73(4): 472 - 481. [Abstract] [Full Text] [PDF]
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 C Kreiss, L A Birder, S Kiss, M M VanBibber, and A J Bauer COX-2 dependent inflammation increases spinal Fos expression during rodent postoperative ileus Gut, April 1, 2003; 52(4): 527 - 534. [Abstract] [Full Text] [PDF]
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D. Komninou, A. Ayonote, J. P. Richie Jr., and B. Rigas Insulin Resistance and Its Contribution to Colon Carcinogenesis Exp Biol Med, April 1, 2003; 228(4): 396 - 405. [Abstract] [Full Text] [PDF]
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T. Takano, A. V. Cybulsky, W. A. Cupples, D. O. Ajikobi, J. Papillon, and L. Aoudjit Inhibition of Cyclooxygenases Reduces Complement-Induced Glomerular Epithelial Cell Injury and Proteinuria in Passive Heymann Nephritis J. Pharmacol. Exp. Ther., April 1, 2003; 305(1): 240 - 249. [Abstract] [Full Text]
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 L. Zou, B. Attuwaybi, and B. C. Kone Effects of NF-kappa B inhibition on mesenteric ischemia-reperfusion injury Am J Physiol Gastrointest Liver Physiol, April 1, 2003; 284(4): G713 - G721. [Abstract] [Full Text] [PDF]
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N. A. Callejas, A. Fernandez-Martinez, A. Castrillo, L. Bosca, and P. Martin-Sanz Selective Inhibitors of Cyclooxygenase-2 Delay the Activation of Nuclear Factor kappa B and Attenuate the Expression of Inflammatory Genes in Murine Macrophages Treated with Lipopolysaccharide Mol. Pharmacol., March 1, 2003; 63(3): 671 - 677. [Abstract] [Full Text] [PDF]
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D. M. Aronoff, O. Boutaud, L. J. Marnett, and J. A. Oates Inhibition of Prostaglandin H2 Synthases by Salicylate Is Dependent on the Oxidative State of the Enzymes J. Pharmacol. Exp. Ther., February 1, 2003; 304(2): 589 - 595. [Abstract] [Full Text] [PDF]
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J. C. Desmond, J. C. Mountford, M. T. Drayson, E. A. Walker, M. Hewison, J. P. Ride, Q. T. Luong, R. E. Hayden, E. F. Vanin, and C. M. Bunce The Aldo-Keto Reductase AKR1C3 Is a Novel Suppressor of Cell Differentiation That Provides a Plausible Target for the Non-Cyclooxygenase-dependent Antineoplastic Actions of Nonsteroidal Anti-Inflammatory Drugs Cancer Res., January 15, 2003; 63(2): 505 - 512. [Abstract] [Full Text] [PDF]
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 V. Blais, J. Zhang, and S. Rivest In Altering the Release of Glucocorticoids, Ketorolac Exacerbates the Effects of Systemic Immune Stimuli on Expression of Proinflammatory Genes in the Brain Endocrinology, December 1, 2002; 143(12): 4820 - 4827. [Abstract] [Full Text] [PDF]
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 D. M. Duffy and R. L. Stouffer Follicular administration of a cyclooxygenase inhibitor can prevent oocyte release without alteration of normal luteal function in rhesus monkeys Hum. Reprod., November 1, 2002; 17(11): 2825 - 2831. [Abstract] [Full Text] [PDF]
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M. Wick, G. Hurteau, C. Dessev, D. Chan, M. W. Geraci, R. A. Winn, L. E. Heasley, and R. A. Nemenoff Peroxisome Proliferator-Activated Receptor-gamma Is a Target of Nonsteroidal Anti-Inflammatory Drugs Mediating Cyclooxygenase-Independent Inhibition of Lung Cancer Cell Growth Mol. Pharmacol., November 1, 2002; 62(5): 1207 - 1214. [Abstract] [Full Text] [PDF]
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L. R. Kisley, B. S. Barrett, L. D. Dwyer-Nield, A. K. Bauer, D. C. Thompson, and A. M. Malkinson Celecoxib reduces pulmonary inflammation but not lung tumorigenesis in mice Carcinogenesis, October 1, 2002; 23(10): 1653 - 1660. [Abstract] [Full Text] [PDF]
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V. E. L. Stubbs, P. Schratl, A. Hartnell, T. J. Williams, B. A. Peskar, A. Heinemann, and I. Sabroe Indomethacin Causes Prostaglandin D2-like and Eotaxin-like Selective Responses in Eosinophils and Basophils J. Biol. Chem., July 12, 2002; 277(29): 26012 - 26020. [Abstract] [Full Text] [PDF]
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R. Yamazaki, N. Kusunoki, T. Matsuzaki, S. Hashimoto, and S. Kawai Nonsteroidal Anti-Inflammatory Drugs Induce Apoptosis in Association with Activation of Peroxisome Proliferator-Activated Receptor gamma in Rheumatoid Synovial Cells J. Pharmacol. Exp. Ther., July 1, 2002; 302(1): 18 - 25. [Abstract] [Full Text] [PDF]
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 J. Sadoshima Novel AT1 Receptor-Independent Functions of Losartan Circ. Res., April 19, 2002; 90(7): 754 - 756. [Full Text] [PDF]
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