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Cyclooxygenase-2 independent effects of cyclooxygenase-2 inhibitors on oxidative stress and intracellular glutathione content in normal and malignant human B-cells

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Abstract

We recently reported that inhibition of Cyclooxygenase-2 (Cox-2) reduced human B-CLL proliferation and survival. Herein, we investigated the mechanisms whereby small molecule Cox-2 selective inhibitors, SC-58125 (a Celebrex analog) and CAY10404 blunt survival of human B-cell lymphomas and chronic lymphocytic leukemia B-cells. SC-58125 and OSU03012 (a Celebrex analog that lacks Cox-2 inhibitory activity) both decreased intracellular glutathione (GSH) content in malignant human B-cells, as well as in Cox-2 deficient mouse B-cells. This new finding supports Cox-2 independent effects of SC-58125. Interestingly, SC-58125 also significantly increased B-cell reactive oxygen species (ROS) production, suggesting that ROS are a pathway that reduces malignant cell survival. Addition of GSH ethyl ester protected B lymphomas from the increased mitochondrial membrane permeability and reduced survival induced by SC-58125. Moreover, the SC-58125-mediated GSH depletion resulted in elevated steady-state levels of the glutamate cysteine ligase catalytic subunit mRNA and protein. These new findings of increased ROS and diminished GSH levels following SC-58125 exposure support novel mechanisms whereby a Cox-2 selective inhibitor reduces malignant B-cell survival. These observations also support the concept that certain Cox-2 selective inhibitors may have therapeutic value in combination with other drugs to kill malignant B lineage cells.

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Abbreviations

Cox-2:

Cyclooxygenase-2

GSH:

Glutathione

ROS:

Reactive oxygen species

GCL:

Glutamate cysteine ligase

References

  1. Singh B, Berry JA, Shoher A, Ramakrishnan V, Lucci A (2005) COX-2 overexpression increases motility and invasion of breast cancer cells. Int J Oncol 26:1393–1399

    PubMed  CAS  Google Scholar 

  2. Chen Q, Shinohara N, Abe T, Watanabe T, Nonomura K, Koyanagi T (2004) Significance of COX-2 expression in human renal cell carcinoma cell lines. Int J Cancer 108:825–832

    Article  PubMed  CAS  Google Scholar 

  3. Dubois RN (2000) Review article: cyclooxygenase—a target for colon cancer prevention. Aliment Pharmacol Ther 14(Suppl 1):64–67

    Article  PubMed  CAS  Google Scholar 

  4. Samoha S, Arber N (2005) Cyclooxygenase-2 inhibition prevents colorectal cancer: from the bench to the bed side. Oncology 69(Suppl 1):33–37

    Article  PubMed  CAS  Google Scholar 

  5. Nakao S, Kuwano T, Tsutsumi-Miyahara C, Ueda S, Kimura YN, Hamano S, Sonoda KH, Saijo Y, Nukiwa T, Strieter RM, Ishibashi T, Kuwano M, Ono M (2005) Infiltration of COX-2-expressing macrophages is a prerequisite for IL-1beta-induced neovascularization and tumor growth. J Clin Invest 115:2979–2991

    Article  PubMed  CAS  Google Scholar 

  6. Zhi YH, Liu RS, Song MM, Tian Y, Long J, Tu W, Guo RX (2005) Cyclooxygenase-2 promotes angiogenesis by increasing vascular endothelial growth factor and predicts prognosis in gallbladder carcinoma. World J Gastroenterol 11:3724–3728

    PubMed  CAS  Google Scholar 

  7. Ito H, Duxbury M, Benoit E, Clancy TE, Zinner MJ, Ashley SW, Whang EE (2004) Prostaglandin E2 enhances pancreatic cancer invasiveness through an Ets-1-dependent induction of matrix metalloproteinase-2. Cancer Res 64:7439–7446

    Article  PubMed  CAS  Google Scholar 

  8. Park JH, Kang KH, Kim SH, Lee JH, Cho CM, Kweon YO, Kim SK, Choi YH, Bae HI, Kim MS (2005) Expression of Cyclooxygenase-2 and Bcl-2 in human gastric adenomas. Korean J Intern Med 20:198–204

    PubMed  CAS  Google Scholar 

  9. Charames GS, Bapat B (2006) Cyclooxygenase-2 knockdown by RNA interference in colon cancer. Int J Oncol 28:543–549

    PubMed  CAS  Google Scholar 

  10. Han S, Roman J (2006) COX-2 inhibitors suppress lung cancer cell growth by inducing p21 via COX-2 independent signals. Lung Cancer 51(3):283–296

    Article  PubMed  Google Scholar 

  11. Palayoor ST, Arayankalayil MJ, Shoaibi A, Coleman CN (2005) Radiation sensitivity of human carcinoma cells transfected with small interfering RNA Targeted against cyclooxygenase-2. Clin Cancer Res 11:6980–6986

    Article  PubMed  CAS  Google Scholar 

  12. Arico S, Pattingre S, Bauvy C, Gane P, Barbat A, Codogno P, Ogier-Denis E (2002) Celecoxib induces apoptosis by inhibiting 3-phosphoinositide-dependent protein kinase-1 activity in the human colon cancer HT-29 cell line. J Biol Chem 277:27613–27621

    Article  PubMed  CAS  Google Scholar 

  13. Johnson AJ, Hsu AL, Lin HP, Song X, Chen CS (2002) The cyclo-oxygenase-2 inhibitor celecoxib perturbs intracellular calcium by inhibiting endoplasmic reticulum Ca2+-ATPases: a plausible link with its anti-tumour effect and cardiovascular risks. Biochem J 366:831–837

    PubMed  CAS  Google Scholar 

  14. Maier TJ, Janssen A, Schmidt R, Geisslinger G, Grosch S (2005) Targeting the beta-catenin/APC pathway: a novel mechanism to explain the cyclooxygenase-2-independent anticarcinogenic effects of celecoxib in human colon carcinoma cells. Faseb J 19:1353–1355

    PubMed  CAS  Google Scholar 

  15. Weber A, Casini A, Heine A, Kuhn D, Supuran CT, Scozzafava A, Klebe G (2004) Unexpected nanomolar inhibition of carbonic anhydrase by COX-2-selective celecoxib: new pharmacological opportunities due to related binding site recognition. J Med Chem 47:550–557

    Article  PubMed  CAS  Google Scholar 

  16. Zhu J, Song X, Lin HP, Young DC, Yan S, Marquez VE, Chen CS (2002) Using cyclooxygenase-2 inhibitors as molecular platforms to develop a new class of apoptosis-inducing agents. J Natl Cancer Inst 94:1745–1757

    PubMed  CAS  Google Scholar 

  17. Phipps RP, Ryan E, Bernstein SH (2004) Inhibition of cyclooxygenase-2: a new targeted therapy for B-cell lymphoma? Leuk Res 28:109–111

    Article  PubMed  CAS  Google Scholar 

  18. Hazar B, Ergin M, Seyrek E, Erdogan S, Tuncer I, Hakverdi S (2004) Cyclooxygenase-2 (Cox-2) expression in lymphomas. Leuk Lymphoma 45:1395–1399

    Article  PubMed  CAS  Google Scholar 

  19. Wun T, McKnight H, Tuscano JM (2004) Increased cyclooxygenase-2 (COX-2): a potential role in the pathogenesis of lymphoma. Leuk Res 28:179–190

    Article  PubMed  CAS  Google Scholar 

  20. Secchiero P, Barbarotto E, Gonelli A, Tiribelli M, Zerbinati C, Celeghini C, Agostinelli C, Pileri SA, Zauli G (2005) Potential pathogenetic implications of cyclooxygenase-2 overexpression in B chronic lymphoid leukemia cells. Am J Pathol 167:1599–1607

    PubMed  CAS  Google Scholar 

  21. Ryan EP, Pollock SJ, Kaur K, Felgar RE, Bernstein SH, Chiorrazi N, Phipps RP (2006) Constitutive and activation-inducible cyclooxygenase-2 expression enhances survival of chronic lymphocytic leukemia B cells. Clin Immunol 120(1):76–90

    Article  PubMed  CAS  Google Scholar 

  22. Armstrong JS, Steinauer KK, Hornung B, Irish JM, Lecane P, Birrell GW, Peehl DM, Knox SJ (2002) Role of glutathione depletion and reactive oxygen species generation in apoptotic signaling in a human B lymphoma cell line. Cell Death Differ 9:252–263

    Article  PubMed  CAS  Google Scholar 

  23. Ferraris AM, Rolfo M, Mangerini R, Gaetani GF (1994) Increased glutathione in chronic lymphocytic leukemia lymphocytes. Am J Hematol 47:237–238

    Article  PubMed  CAS  Google Scholar 

  24. Margalit A, Hauser SD, Zweifel BS, Anderson MA, Isakson PC (1998) Regulation of prostaglandin biosynthesis in vivo by glutathione. Am J Physiol 274:R294–R302

    PubMed  CAS  Google Scholar 

  25. Pompella A, Visvikis A, Paolicchi A, De Tata V, Casini AF (2003) The changing faces of glutathione, a cellular protagonist. Biochem Pharmacol 66:1499–1503

    Article  PubMed  CAS  Google Scholar 

  26. Fedyk ER, Phipps RP (1994) Reactive oxygen species and not lipoxygenase products are required for mouse B-lymphocyte activation and differentiation. Int J Immunopharmacol 16:533–546

    Article  PubMed  CAS  Google Scholar 

  27. Padilla J, Leung E, Phipps RP (2002) Human B lymphocytes and B lymphomas express PPAR-gamma and are killed by PPAR-gamma agonists. Clin Immunol 103:22–33

    Article  PubMed  CAS  Google Scholar 

  28. Ryan EP, Pollack SJ, Murant TI, Bernstein SH, Felgar RE, Phipps RP (2005) Activated human B lymphocytes express cyclooxygenase-2 and cyclooxygenase inhibitors attenuate antibody production. J Immunol 174:2619–2626

    PubMed  CAS  Google Scholar 

  29. Kehry MR, Castle BE (1994) Regulation of CD40 ligand expression and use of recombinant CD40 ligand for studying B cell growth and differentiation. Semin Immunol 6:287–294

    Article  PubMed  CAS  Google Scholar 

  30. Capone ML, Tacconelli S, Sciulli MG, Patrignani P (2003) Clinical pharmacology of selective COX-2 inhibitors. Int J Immunopathol Pharmacol 16:49–58

    PubMed  CAS  Google Scholar 

  31. Johnson AJ, Smith LL, Zhu J, Heerema NA, Jefferson S, Mone A, Grever M, Chen CS, Byrd JC (2005) A novel celecoxib derivative, OSU03012, induces cytotoxicity in primary CLL cells and transformed B-cell lymphoma cell line via a caspase- and Bcl-2-independent mechanism. Blood 105:2504–2509

    Article  PubMed  CAS  Google Scholar 

  32. Eady JJ, Orta T, Dennis MF, Stratford MR, Peacock JH (1995) Glutathione determination by the Tietze enzymatic recycling assay and its relationship to cellular radiation response. Br J Cancer 72:1089–1095

    PubMed  CAS  Google Scholar 

  33. Staal FJ, Roederer M, Herzenberg LA, Herzenberg LA (1990) Intracellular thiols regulate activation of nuclear factor kappa B and transcription of human immunodeficiency virus. Proc Natl Acad Sci USA 87:9943–9947

    Article  PubMed  CAS  Google Scholar 

  34. Cerimele F, Battle T, Lynch R, Frank DA, Murad E, Cohen C, Macaron N, Sixbey J, Smith K, Watnick RS, Eliopoulos A, Shehata B, Arbiser JL (2005) Reactive oxygen signaling and MAPK activation distinguish Epstein-Barr Virus (EBV)-positive versus EBV-negative Burkitt’s lymphoma. Proc Natl Acad Sci USA 102:175–179

    Article  PubMed  CAS  Google Scholar 

  35. Zhou Y, Hileman EO, Plunkett W, Keating MJ, Huang P (2003) Free radical stress in chronic lymphocytic leukemia cells and its role in cellular sensitivity to ROS-generating anticancer agents. Blood 101:4098–4104

    Article  PubMed  CAS  Google Scholar 

  36. George TC, Fanning SL, Fitzgeral-Bocarsly P, Medeiros RB, Highfill S, Shimizu Y, Hall BE, Frost K, Basiji D, Ortyn WE, Morrissey PJ, Lynch DH (2006) Quantitative measurement of nuclear translocation events using similarity analysis of multispectral cellular images obtained in flow. J Immunol Methods 311:117–129

    Article  PubMed  CAS  Google Scholar 

  37. Ortyn WE, Hall BE, George TC, Frost K, Basiji DA, Perry DJ, Zimmerman CA, Coder D, Morrissey PJ (2006) Sensitivity measurement and compensation in spectral imaging. Cytometry A 69:852–862

    PubMed  Google Scholar 

  38. Ray DM, Akbiyik F, Phipps RP (2006) The peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) ligands 15-deoxy-{delta}12,14-prostaglandin J2 and ciglitazone induce human B lymphocyte and B cell lymphoma apoptosis by PPAR{gamma}-independent mechanisms. J Immunol 177:5068–5076

    PubMed  CAS  Google Scholar 

  39. Inoue H, Takemura H, Kawai Y, Yoshida A, Ueda T, Miyashita T (2002) Dexamethasone-resistant human Pre-B leukemia 697 cell line evolving elevation of intracellular glutathione level: an additional resistance mechanism. Jpn J Cancer Res 93:582–590

    PubMed  CAS  Google Scholar 

  40. Seelig GF, Simondsen RP, Meister A (1984) Reversible dissociation of gamma-glutamylcysteine synthetase into two subunits. J Biol Chem 259:9345–9347

    PubMed  CAS  Google Scholar 

  41. Rahman I, Bel A, Mulier B, Lawson MF, Harrison DJ, Macnee W, Smith CA (1996) Transcriptional regulation of gamma-glutamylcysteine synthetase-heavy subunit by oxidants in human alveolar epithelial cells. Biochem Biophys Res Commun 229:832–837

    Article  PubMed  CAS  Google Scholar 

  42. Schumacker PT (2006) Reactive oxygen species in cancer cells: live by the sword, die by the sword. Cancer Cell 10:175–176

    Article  PubMed  CAS  Google Scholar 

  43. Ding H, Han C, Zhu J, Chen CS, D’Ambrosio SM (2005) Celecoxib derivatives induce apoptosis via the disruption of mitochondrial membrane potential and activation of caspase 9. Int J Cancer 113:803–810

    Article  PubMed  CAS  Google Scholar 

  44. Jendrossek V, Handrick R, Belka C (2003) Celecoxib activates a novel mitochondrial apoptosis signaling pathway. Faseb J 17:1547–1549

    PubMed  CAS  Google Scholar 

  45. Johnson AJ, Smith LL, Zhu J, Heerema NA, Jefferson S, Mone A, Grever M, Chen CS, Byrd JC (2005) A novel celecoxib derivative, OSU03012, induces cytotoxicity in primary CLL cells and transformed B-cell lymphoma via a caspase and Bcl-2 independent mechanism. Blood 15; 105(6):2504–2509

    Google Scholar 

  46. Zhong H, Willard M, Simons J (2004) NS398 reduces hypoxia-inducible factor (HIF)-1alpha and HIF-1 activity: multiple-level effects involving cyclooxygenase-2 dependent and independent mechanisms. Int J Cancer 112:585–595

    Article  PubMed  CAS  Google Scholar 

  47. Carew JS, Zhou Y, Albitar M, Carew JD, Keating MJ, Huang P (2003) Mitochondrial DNA mutations in primary leukemia cells after chemotherapy: clinical significance and therapeutic implications. Leukemia 17:1437–1447

    Article  PubMed  CAS  Google Scholar 

  48. Nilsson J, Soderberg O, Nilsson K, Rosen A (2004) Differentiation-associated redox-regulation in human B cell lines from stem cell/pro-B to plasma cell. Immunol Lett 94:83–89

    Article  PubMed  CAS  Google Scholar 

  49. Tsujii M, Kawano S, Tsuji S, Sawaoka H, Hori M, DuBois RN (1998) Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell 93:705–716

    Article  PubMed  CAS  Google Scholar 

  50. Chu AJ, Chou TH, Chen BD (2004) Prevention of colorectal cancer using COX-2 inhibitors: basic science and clinical applications. Front Biosci 9:2697–2713

    Article  PubMed  CAS  Google Scholar 

  51. Chang ET, Zheng T, Weir EG, Borowitz M, Mann RB, Spiegelman D, Mueller NE (2004) Aspirin and the risk of Hodgkin’s lymphoma in a population-based case-control study. J Natl Cancer Inst 96:305–315

    Article  PubMed  CAS  Google Scholar 

  52. Beiderbeck AB, Holly EA, Sturkenboom MC, Coebergh JW, Stricker BH, Leufkens HG (2003) Prescription medications associated with a decreased risk of non-Hodgkin’s Lymphoma. Am J Epidemiol 157:510–516

    Google Scholar 

  53. Ellen T, Chang KEmS, Henrik Hjalgrim, Claudia Schöllkopf, Anna, Porwit-MacDonald CSm, Edneia Tani, Francesco d’Amore, Mads Melbye, Hans-Olov Adami aBG (2005) Medication use and risk of non-Hodgkin’s Lymphoma. Am J Epidemiol 162:965–974

    Google Scholar 

  54. Rao CV, Reddy BS (2004) NSAIDs and chemoprevention. Curr Cancer Drug Targets 4:29–42

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by the following NIH grants DE011390, ES01247, HL078603, T32-ES07026, AI071064 and R25CA102618 and a grant from the Leukemia and Lymphoma Society at the James P. Wilmot Foundation.

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Authors and Affiliations

  1. Department of Environmental Medicine, Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 850, Rochester, NY, 14642, USA

    Elizabeth P. Ryan, Alan E. Friedman, Irfan Rahman & Richard P. Phipps

  2. Department of Pediatrics, Center for Pediatric Biomedical Research, University of Rochester School of Medicine and Dentistry, Rochester, NY, 14642, USA

    Timothy P. Bushnell

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  1. Elizabeth P. Ryan
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  2. Timothy P. Bushnell
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  3. Alan E. Friedman
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  5. Richard P. Phipps
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Correspondence to Richard P. Phipps.

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Ryan, E.P., Bushnell, T.P., Friedman, A.E. et al. Cyclooxygenase-2 independent effects of cyclooxygenase-2 inhibitors on oxidative stress and intracellular glutathione content in normal and malignant human B-cells. Cancer Immunol Immunother 57, 347–358 (2008). https://doi.org/10.1007/s00262-007-0374-4

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