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tNOX, an alternative target to COX-2 to explain the anticancer activities of non-steroidal anti-inflammatory drugs (NSAIDS)

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Abstract

Our work has identified a cancer-specific, cell surface and growth-related quinol oxidase with both NADH oxidase and protein disulfide-thiol interchange activities, a member of the ECTO-NOX protein family designated tNOX. We provide evidence for tNOX as an alternative drug target to COX-2 to explain the anticancer activity of COX inhibitors. Non-steroidal anti-inflammatory drugs (NSAIDS), piroxicam, aspirin, ibuprofen, naproxen and celecoxib all specifically inhibited tNOX activity of HeLa (human cervical carcinoma) and BT-20 (human mammary carcinoma) cells (IC50 in the nanomolar range) without effect on ECTO-NOX activities of non-cancer MCF-10A mammary epithelial cells. With cancer cells, rofecoxib was less effective and two NSAIDS selective for COX-1 were without effect in inhibiting NOX activity. The IC50 for inhibition of tNOX activity of HeLa cells and the IC50 for inhibition of growth of HeLa cells in culture were closely correlated. The findings provide evidence for a new drug target to account for anticancer effects of NSAIDS that occur independent of COX-2.

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References

  1. Dannenberg AJ, Subbaramaiah K: Targeting cyclooxygenase-2 in human neoplasia: rationale and promise. Cancer Cell 4: 431–436, 2003

    Article  CAS  PubMed  Google Scholar 

  2. Moore BC, Simmons DL: COX-2 inhibition, apoptosis, and chemoprevention by nonsteroidal anti-inflammatory drugs. Curr Med Chem 7: 1131–1144, 2000

    CAS  PubMed  Google Scholar 

  3. Thun MJ, Henley SJ, Patrono C: Nonsteroidal anti-inflammatory drugs as anticancer agents: Mechanistic, pharmacologic, and clinical issues. J Natl Cancer Inst 94: 252–266, 2002

    CAS  PubMed  Google Scholar 

  4. Rahme E, Barkun AN, Toubouti Y, Bardou M: The cyclooxygenase-2-selective inhibitors rofecoxib and celecoxib prevent colorectal neoplasia occurrence and recurrence. Gastroenterology 125: 404–412, 2003

    Article  CAS  PubMed  Google Scholar 

  5. Liu CH, Chang SH, Narko K, Trifan OC, Wu MT, Smith E, Haudenschild C, Lane TF, Hia T: Overexpression of COX-2 is sufficient to induce tumorigenesis in transgenic mice. J Biol Chem 276: 18563–18569, 2001

    CAS  PubMed  Google Scholar 

  6. Neufang G, Furstenberger G, Heidt M, Marks F, Muller-Decker K: Abnormal differentiation of epidermis in transgenic mice constitutively expressing cyclooxygenase-2 in skin. Proc Natl Acad Sci USA 98: 7629–7634, 2001

    Article  CAS  PubMed  Google Scholar 

  7. Kazanov D, Dvory-Sobol H, Pick M, Liberman E, Strier L, Choen-Noyman E, Deutsch V, Kunik T, Arber N: Celecoxib but not rofecoxib inhibits the growth of transformed cells in vitro. Clin Can Res 10: 267–271, 2004

    CAS  Google Scholar 

  8. Patel MI, Subbaramaiah K, Du B, Chang M, Yang P, Newman RA, Cordon-Cardo C, Thaler HT, Dannenberg AJ: Celecoxib inhibits prostate cancer growth: Evidence of a cyclooxygenase-2-independent mechanism. Clin Can Res 11: 1999–2007, 2005

    CAS  Google Scholar 

  9. Waskewich C, Blumenthal RD, Li H, Stein R, Goldenberg DM, Burton J: Celecoxib exhibits the greatest potency amongst cyclooxygenase (COX) inhibitors for growth inhibition of COX-2-negative hematopoietic and epithelial cell lines. Cancer Res 62: 2029–2033, 2002

    CAS  PubMed  Google Scholar 

  10. Morré DJ, Morré DM: Cell surface NADH oxidase (ECTO-NOX proteins) with roles in cancer, cellular time-keeping, growth, aging and neurodegenerative diseases. Free Rad Res 37: 759–808, 2003

    Google Scholar 

  11. Smith PK, Krohn RI, Hermanson GT, Mallia AK, Gartner RH, Provenzano EK, Fujimoto EK, Goeke NM, Olson BJ, Klenk DC: Measurement of protein using bicinchoninic acid. Anal Biochem 150: 76–85, 1985

    Article  CAS  PubMed  Google Scholar 

  12. Morré DJ: NADH oxidase: a multifunctional ectoprotein of the eukaryotic cell surface. In: H. Asard, A. Bérczi, R. Caubergs (eds). Plasma membrane redox systems and their role in biological stress and disease. Kluwer Academic Publishers, Dordrecht, The Netherlands, 1998 pp. 121–156

    Google Scholar 

  13. Morré DJ, Morré DM: Synergistic Capsicum-tea mixtures with anticancer activity. J Pharm Pharmacol 55: 987–994, 2003

    Article  PubMed  Google Scholar 

  14. Sedlak D, Morré DM, Morré DJ: A drug-unresponsive and protease-resistant CNOX protein from human sera. Arch Biochem Biophys 386: 106–116, 2001

    Article  CAS  PubMed  Google Scholar 

  15. Lin YL, Juan IM, Chen YL, Liang YC, Lin JK: Composition of polyphenols in fresh tea leaves and associations of their oxygen-radical-absorbing capacity with antiproliferative actions in fibroblast cells. J Agric Food Chem 44: 1387–1394, 1996

    Article  CAS  Google Scholar 

  16. Morré DJ, Chueh P-J, Morré DM: Capsaicin inhibits preferentially the NADH oxidase and growth of transformed cells in culture. Proc Natl Acad Sci USA 92: 1821–1835, 1995

    Google Scholar 

  17. North GL: Celecoxib as adjunctive therapy for treatment of colorectal cancer. An Pharmacother 35: 1638–1643, 2001

    CAS  Google Scholar 

  18. Chueh P-J, Kim C, Cho N, Morré DM, Morré DJ: Molecular cloning and characterization of a tumor-associated, growth-related and time-keeping hydroquinone (NADH) oxidase (NOX) of the HeLa cell surface. Biochemistry 41: 3732–3741, 2002

    Article  CAS  PubMed  Google Scholar 

  19. Chueh P-J, Wu L-Y, Morré DM, Morré DJ: tNOX is both necessary and sufficient as a cellular target for the anticancer actions of capsaicin and the green tea catechin (−) epigallocatechin gallate. BioFactors 20: 249–263, 2004

    CAS  Google Scholar 

  20. Morré DJ, Bridge A, Wu L-Y, Morré DM: Epigallocatechin gallate inhibits preferentially the NADH oxidase and growth of transformed cells in culture. Biochem Pharmacol 60: 937–946, 2000

    Article  PubMed  Google Scholar 

  21. Morré DM, Morré DJ: Mechanism of killing of HeLa cells by the antitumor sulfonylurea N-(4-methylphenylsulfonyl)-N′-(4-chlorophenyl)urea (LY181984). Protoplasma 184: 188–195, 1995

    Google Scholar 

  22. Tang X, Tian Z, Chueh P-J, Chen S, Morré DM, Morré DJ: Alternative splicing as the basis for specific localization of tNOX, a unique hydroquinone (NADH) oxidase, to the cancer cell surface. In preparation

  23. Morré DJ, Morré DM, Su H, Cooper R, Chang J, Janle EM: Tea catechin synergies in inhibition of cancer cell proliferation and of a cancer specific cell surface oxidase (ECTO-NOX). Pharmcol Toxicol 92: 234–241, 2003

    Google Scholar 

  24. Wu KK: Aspirin and other cyclooxygenase inhibitors: new therapeutic insights. Semin Vasc Med 3: 107–112, 2003

    PubMed  Google Scholar 

  25. Ochi T, Goto T: Differential effect of FR122047, a selective cyclo-oxygenase-1 inhibitor, in rat chronic models of arthritis. Br J Pharmacol 135: 782–788, 2002

    Article  CAS  PubMed  Google Scholar 

  26. Szewczuk LM, Forti L, Stivala LA, Penning TM: Resveratrol is a peroxidase-mediated inactivator of COX-1 but not COX-2: a mechanistic approach to the design of COX-1 selective agents. J Biol Chem 279: 22727–22737, 2004

    Article  CAS  PubMed  Google Scholar 

  27. Gerhauser C, Alt A, Heiss E, Gamal-Eldeen A, Klimo K, Knauft J, Neumann I, Scherf HR, Frank N, Bartsch H, Becker H: Cancer chemopreventive activity of xanthohumol, a natural product derived from hops. Mol Cancer Ther 1: 959–969, 2002

    CAS  PubMed  Google Scholar 

  28. Stevens JF, Page JE: Xanthohumol and related prenylflavonoids from hops and beer. Phytochemistry 65: 1317–1330, 2004

    Article  CAS  PubMed  Google Scholar 

  29. Chulada PC, Thompson MB, Mahler JF, Doyle CM, Gaul BW, Lee C, Tiano HF, Morham SG, Smithies O, Langenbach R: Genetic disruption of Ptgs-1, as well as of Ptgs-2, reduces intestinal tumorigenesis in Min mice. Cancer Res 60: 4705–4708, 2000

    CAS  PubMed  Google Scholar 

  30. Subbaramaiah K, Dannenberg AJ: Cyclooxygenase 2: a molecular target for cancer prevention and treatment. Trends Pharmacol Sci 24: 96–102, 2003

    Article  CAS  PubMed  Google Scholar 

  31. Williams CS, Tsujii M, Reese J, Dey SK, DuBoise RN: Host cyclooxygenase-2 modulates carcinoma growth. J Clin Invest 105: 1589–1594, 2000

    CAS  PubMed  Google Scholar 

  32. Ristimaki A, Sivula A, Lundin J, Lundin M, Salminen T, Haglund C, Joensuu H, Isola J: Prognostic significance of elevated cyclooxygenase-2 expression in breast cancer. Cancer Res 62: 632–635, 2002

    CAS  PubMed  Google Scholar 

  33. Bosett C, Gallus S, La Vecchia C: Aspirin and cancer risk: an update to 2001. Eur J Cancer Prev 11: 535–542, 2002

    Google Scholar 

  34. Yu HG, Huang JA, Yang YN, Huang H, Luo HS, Yu JP, Schrader H, Bastian A, Schmidt WE, Schmitz F: The effects of acetylsalicylic acid on proliferation, apoptosis, and invasion of cyclooxygenase-2 negative colon cancer cells. Eur J Clin Invest 32: 838–846, 2002

    Article  CAS  PubMed  Google Scholar 

  35. Ratnasinghe LD, Graubard BI, Kahle L, Tangrea JA, Taylor PR, Hawk E: Aspirin use and mortality from cancer in a prospective cohort study Anticancer Res 24: 3177–3184, 2004

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana, USA

    D. James Morré

  2. Department of Foods and Nutrition, Purdue University, West Lafayette, Indiana, USA

    Dorothy M. Morre

  3. Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 201 South University Street, West Lafayette, IN, 47907-2064, USA

    D. James Morré

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  1. D. James Morré
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Correspondence to D. James Morré.

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Morré, D.J., Morre, D.M. tNOX, an alternative target to COX-2 to explain the anticancer activities of non-steroidal anti-inflammatory drugs (NSAIDS). Mol Cell Biochem 283, 159–167 (2006). https://doi.org/10.1007/s11010-006-2568-z

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  • DOI: https://doi.org/10.1007/s11010-006-2568-z

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