Journal of Veterinary Clinics (한국임상수의학회지)

The Korean Society of Veterinary Clinics (한국임상수의학회)
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Production of Reactive Oxygen Species and Nitric Oxide by Anticancer Agents in Rat Polymorphonuclear Leukocytes

항암제에 의한 흰쥐 다형핵백혈구의 활성산소종(reactive oxygen species) 및 산화질소(nitric oxide)의 생성

  • Kang, Dong-Joon (College of Veterinary Medicine, Konkuk University) ;
  • Song, Seung-Hee (Changwon College) ;
  • Kim, Cheol-Ho (Livestock Promotion Institute) ;
  • Lee, Sang-Kil (College of Veterinary Medicine (The Institute of Animal Medicine), Gyeongsang National University) ;
  • Kang, Chung-Boo (College of Veterinary Medicine (The Institute of Animal Medicine), Gyeongsang National University)
  • Published : 2009.02.27
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Abstract

The production of reactive oxygen species (ROS) and nitric oxide (NO) by anticancer agents in rat polymorphonuclear leukocytes (PMN) was examined. PMN treated for short term (< or = 4 h) with cyclophosphamide, cisplatin, tamoxifen and doxifluridine, respectively, exhibited an enhanced respiratory burst upon formylmethionylleucy1-phenylalanine (FMLP) stimulation. In the long term (> 4h), the production of ROS was suppressed in a concentration-dependent manner. The production of superoxide anion (${O_2}^-$) from the FMLP-stimulated PMN was enhanced by the treatment (for 1 hr) of cyclophosphamide, cisplatin, tamoxifen and doxifluridine, respectively. While 1 hr-treatment with cyclophosphamide, cisplatin, tamoxifen, and doxifluridine, respectively, suppressed the production of NO from the FMLP-stimulated PMN, while 8 hr-treatment enhanced the production of NO. Neomycin suppressed chemiluminescence in cisplatin-, tamoxifen- and doxifluridine-pretreated PMN, however near suppression of chemiluminescence by ethanol and genistein was observed in PMN pretreated with these agents. Staurosporine and bisindolylmaleimide suppressed chemiluminescence in cisplatin- and doxifluridine- pretreated PMN. Wortmannin has shown a slight suppression in cyclophosphamide-, cisplatin- and tamoxifen-pretreated PMN, but a strong suppression in doxifluridine-pretreated PMN. Methionine strongly suppressed in cyclophosphamide and cisplatin-pretreated PMN. In conclusion, these results indicate that long term treatment of PMN with cisplatin and doxifluridine inhibit respiratory burst through protein kinase C (PKC) translocation, phospholipase C (PLC), D (PLD) and tyrosine phosphorylation kinase (TPK) activation. Tamoxifen inhibits respiratory burst through PLC, PLD, TPK. Cyclophosphamide inhibits respiratory burst through myeloperoxidase (MPO) activity.

항암제에 의해 흰쥐에서 다형핵 백혈구(polymorphonuclear leukocytes, PMN) 의 활성산소종(reactive oxygen species, ROS)과 산화질소(nitric oxide, NO)의 생성변화에 대해 연구하였다. 최근 자극유도인자에 의한 PMN의 호흡방출은 protein kinase C (PKC)의 활성, inositol phosphate transduction pathway의 활성, 그리고 intracellular [$Ca^{2+}$]와 관계가 있다고 밝혀졌으며, 본 연구에서 사용된 항암제(cyclophosphamide, cisplatin, tamoxifen, doxifluridine)중 일부는 화학치료제로써 비특이적으로 면역을 억제하는데 사용되고 있다. 암 치료 시 백혈구의 방어기능에 미치는 영향을 연구하기 위한 목적으로 in vitro에서 각 항암제를 처리한 PMN을 배양하여 ROS와 NO의 생성변화와 이차적 신호전달계인 phospholipase C(PLC), D(PLD), PKC, tyrosine phosphorylation kinase (TPK)와 phosphatidylinositol-3 kinase의 억제율을 측정하였다. PMN에 각각cyclophosphamide, cisplatin, tamoxifen, doxifluridine을 short term(${\leq}4hrs$) 처리시, formylmethionyl-leucy1-phenylalanine (FMLP) 자극에 의해 호흡방출의 증가가 나타났다. 반면, long term (8hrs) 처리 시, ROS의 생성은concentration-dependent 방법으로 감소되었다.

Keywords

References

  1. Aas V, Larsen K, Iversen JG. Interferon-gamma elicits a Gprotein- dependent Ca2+ signal in human neutrophils after depletion of intracellular Ca2+ stores. Cell Signal 1999; 11: 101-110 https://doi.org/10.1016/S0898-6568(98)00040-0
  2. Akimaru K, Utsumi T, Sato EF, Klostergaard J, Inoue M, Utsumi K. Role of tyrosyl phosphorylation in neutrophil priming by tumor necrosis factor-alpha and granulocyte colony stimulating factor. Arch Biochem Biophys 1992; 298: 703-709 https://doi.org/10.1016/0003-9861(92)90469-D
  3. Akiyama T, Ishida J, Nakagawa S, Ogawara H, Watanabe S, Itoh N, Shibuya M, Fukami Y. Genistein, a specific inhibitor of tyrosine-specific protein kinases. J Biol Chem 1987; 262 : 5592-5595
  4. Arcaro A, and Wymann MP. Wortmannin is a potent phosphatidylinositol 3-kinase inhibitor: the role of phosphatidylinositol 3,4,5-trisphosphate in neutrophil responses. Biochem J 1993; 296 ( Pt 2): 297-301
  5. Babior BM. Oxygen-dependent microbial killing by phagocytes (first of two parts). N Engl J Med 1978; 298: 659-668 https://doi.org/10.1056/NEJM197803232981205
  6. Billiar TR., Curran RD., Harbrecht BG., Stuehr DJ., Demetris AJ, and Simmons RL. Modulation of nitrogen oxide synthesis in vivo: NG-monomethyl-L-arginine inhibits endotoxin-induced nitrate/nitrate biosynthesis while promoting hepatic damage. J Leukoc Biol 1990; 48: 565-569
  7. Bit RA, Davis PD, Elliott LH, Harris W, Hill CH, Keech E, Kumar H, Lawton G, Maw A, Nixon JS, David R. Vesey, Julie Wadsworth and Sandra E. Wilkinson. Inhibitors of protein kinase C. 3. Potent and highly selective bisindolylmaleimides by conformational restriction. J Med Chem 1993;36: 21-29 https://doi.org/10.1021/jm00053a003
  8. Bonser RW, Thompson NT, Randall RW, and Garland LG. Phospholipase D activation is functionally linked to superoxide generation in the human neutrophil. Biochem J 1989; 264: 617-620
  9. Carreras MC, Catz SD, Pargament GA, Del Bosco CG, and Poderoso JJ. Decreased production of nitric oxide by human neutrophils during septic multiple organ dysfunction syndrome. Comparison with endotoxin and cytokine effects on normal cells. Inflammation 1994; 18: 151-161 https://doi.org/10.1007/BF01534556
  10. Carreras MC, Riobo NA, Pargament GA, Boveris A, and Poderoso JJ. Effects of respiratory burst inhibitors on nitric oxide production by human neutrophils. Free Radic Res 1997; 26: 325-334 https://doi.org/10.3109/10715769709097812
  11. Chen LW, Shen AY, Chen JS, and Wu SN. Differential regulation of Ca2+ influx by fMLP and PAF in human neutrophils: possible involvement of store-operated Ca2+ channel. Shock 2000; 13: 175-182 https://doi.org/10.1097/00024382-200003000-00002
  12. Cohen HJ, and Chovaniec ME. Superoxide generation by digitonin-stimulated guinea pig granulocytes. A basis for a continuous assay for monitoring superoxide production and for the study of the activation of the generating system. J Clin Invest 1978; 61: 1081-1087 https://doi.org/10.1172/JCI109007
  13. De Sole P, Lippa S, and Littarru GP. Resting and stimulated chemiluminescence of polymorphonuclear leukocytes: a clinical approach. Adv Exp Med Biol 1982; 141: 591-601
  14. DeChatelet LR, Shirley PS, McPhail LC, Iverson DB, and Doellgast GJ. Allosteric transformation of reduced nicotinamide adenine dinucleotide (phosphate) oxidase induced by phagocytosis in human polymorphonuclear leukocytes. Infect Immun 1978; 20: 398-405
  15. Dillon SB, Verghese MW, and Snyderman R. Signal transduction in cells following binding of chemoattractants to membrane receptors. Virchows Arch B Cell Pathol Incl Mol Pathol 1988;55: 65-80 https://doi.org/10.1007/BF02896561
  16. Dooley DC, and Takahashi T. The effect of osmotic stress on the function of the human granulocyte. Exp Hematol 1981; 9: 731-741
  17. Dutton DR, and Bowden GT. Indirect induction of a clastogenic effect in epidermal cells by a tumor promoter. Carcinogenesis 1985; 6: 1279-1284 https://doi.org/10.1093/carcin/6.9.1279
  18. Easmon CS, Cole PJ, Williams AJ, and Hastings M. The measurement of opsonic and phagocytic function by Luminol-dependent chemiluminescence. Immunology 1980; 41: 67-74
  19. Endo M, Shinbori N, Fukase Y, Sawada N, Ishikawa T, Ishitsuka H, and Tanaka Y. Induction of thymidine phosphorylase expression and enhancement of efficacy of capecitabine or 5'-deoxy-5-fluorouridine by cyclophosphamide in mammary tumor models. Int J Cancer 1999; 83: 127-134 https://doi.org/10.1002/(SICI)1097-0215(19990924)83:1<127::AID-IJC22>3.0.CO;2-6
  20. Frenkel K, and Chrzan K. Hydrogen peroxide formation and DNA base modification by tumor promoter-activated polymorphonuclear leukocytes. Carcinogenesis 1987; 8: 455- 460 https://doi.org/10.1093/carcin/8.3.455
  21. Gollin FF, Ansfield FJ, Brandenburg JH, Ramirez G, and Vermund H. Combined therapy in advanced head and neck cancer: a randomized study. Am J Roentgenol Radium Ther Nucl Med 1972; 114: 83-88
  22. Habu H, Yokoi I, Kabuto H, and Mori A. Application of automated flow injection analysis to determine nitrite and nitrate in mouse brain. Neuroreport 1994; 5: 1571-1573 https://doi.org/10.1097/00001756-199408150-00007
  23. Harris J, Sengar D, Stewart T, and Hyslop D. The effect of immunosuppressive chemotherapy on immune function in patients with malignant disease. Cancer 1976; 37: 1058-1069 https://doi.org/10.1002/1097-0142(197602)37:2+<1058::AID-CNCR2820370813>3.0.CO;2-O
  24. Hjorth R, Jonsson AK, and Vretblad P. A rapid method for purification of human granulocytes using percoll. A comparison with dextran sedimentation. J Immunol Methods 1981; 43: 95-101 https://doi.org/10.1016/0022-1759(81)90040-5
  25. Ichinose Y, Hara N, Motohiro A, Noge S, Ohta M, and Yagawa K. Influence of chemotherapy on superoxide aniongenerating activity of polymorphonuclear leukocytes in patients with lung cancer. Cancer 1986; 58: 1663-1667 https://doi.org/10.1002/1097-0142(19861015)58:8<1663::AID-CNCR2820580815>3.0.CO;2-I
  26. Klebanoff SJ. Oxygen metabolism and the toxic properties of phagocytes. Ann Intern Med 1980; 93: 480-489 https://doi.org/10.7326/0003-4819-93-3-480
  27. Koyama H, Nishizawa Y, Noguchi S, Yamamoto H, Miyauchi K, Inaji H, Imaoka S, and Iwanaga T. [Combination therapy with 5'DFUR and MPA as a second line treatment for advanced/recurrent breast cancer]. Nippon Gan Chiryo Gakkai Shi 1990; 25: 655-661
  28. Mandlekar S, and Kong AN. Mechanisms of tamoxifeninduced apoptosis. Apoptosis 2001; 6: 469-477 https://doi.org/10.1023/A:1012437607881
  29. Mitsuyama T, Takeshige K, and Minakami S. Tyrosine phosphorylation is involved in the respiratory burst of electropermeabilized human neutrophils at a step before diacylglycerol formation by phospholipase C. FEBS Lett 1993; 322: 280-284 https://doi.org/10.1016/0014-5793(93)81586-O
  30. Moncada S, Palmer RM, and Higgs EA. Biosynthesis of nitric oxide from L-arginine. A pathway for the regulation of cell function and communication. Biochem Pharmacol 1989; 38: 1709-1715 https://doi.org/10.1016/0006-2952(89)90403-6
  31. Muller-Peddinghaus R. In vitro determination of phagocyte activity by luminol- and lucigenin-amplified chemiluminescence. Int J Immunopharmacol 1984; 6: 455-466 https://doi.org/10.1016/0192-0561(84)90084-5
  32. Mulligan MS, Hevel JM, Marletta MA, and Ward PA. Tissue injury caused by deposition of immune complexes is L-arginine dependent. Proc Natl Acad Sci U S A 1991; 88: 6338-6342 https://doi.org/10.1073/pnas.88.14.6338
  33. Neilly IJ, Copland M, Haj M, Adey G, Benjamin N, and Bennett B. Plasma nitrate concentrations in neutropenic and non-neutropenic patients with suspected septicaemia. Br J Haematol 1995;89: 199-202 https://doi.org/10.1111/j.1365-2141.1995.tb08931.x
  34. Nishihira J, and O'Flaherty JT. Phorbol myristate acetate receptors in human polymorphonuclear neutrophils. J Immunol 1985; 135: 3439-3447
  35. Nussler AK, and Billiar TR. Inflammation, immunoregulation, and inducible nitric oxide synthase. J Leukoc Biol 1993; 54: 171-178
  36. Ochoa JB, Udekwu AO, Billiar TR, Curran RD, Cerra FB, Simmons RL, and Peitzman AB. Nitrogen oxide levels in patients after trauma and during sepsis. Ann Surg 1991; 214: 621-626 https://doi.org/10.1097/00000658-199111000-00013
  37. Rooney M, Kish J, Jacobs J, Kinzie J, Weaver A, Crissman J, and Al-Sarraf M. Improved complete response rate and survival in advanced head and neck cancer after threecourse induction therapy with 120-hour 5-FU infusion and cisplatin. Cancer 1985; 55: 1123-1128 https://doi.org/10.1002/1097-0142(19850301)55:5<1123::AID-CNCR2820550530>3.0.CO;2-8
  38. Sato K, Miyakawa K, Takeya M, Hattori R, Yui Y, Sunamoto M, Ichimori Y, Ushio Y, and Takahashi K. Immunohistochemical expression of inducible nitric oxide synthase (iNOS) in reversible endotoxic shock studied by a novel monoclonal antibody against rat iNOS. J Leukoc Biol 1995; 57: 36-44
  39. Stuehr DJ, Fasehun OA, Kwon NS, Gross SS, Gonzalez JA, Levi R, and Nathan CF. Inhibition of macrophage and endothelial cell nitric oxide synthase by diphenyleneiodonium and its analogs. FASEB J 1991; 5: 98-103
  40. hiemermann C, Wu CC, Szabo C, Perretti M, and Vane J. R. Role of tumour necrosis factor in the induction of nitric oxide synthase in a rat model of endotoxin shock. Br J Pharmacol 1993; 110: 177-182 https://doi.org/10.1111/j.1476-5381.1993.tb13789.x
  41. Thomas EL, Lehrer RI, and Rest RF. Human neutrophil antimicrobial activity. Rev Infect Dis 10 Suppl 1988; 2: S450-456
  42. Ueta E, Osaki T, Yoneda K, and Yamamoto T. Functions of salivary polymorphonuclear leukocytes (SPMNs) and peripheral blood polymorphonuclear leukocytes (PPMNs) from healthy individuals and oral cancer patients. Clin Immunol Immunopathol 1993; 66: 272-278. https://doi.org/10.1006/clin.1993.1036
  43. Ueta E, and Osaki T. Suppression by anticancer agents of reactive oxygen generation from polymorphonuclear leukocytes. Free Radic Res 1996; 24: 39-53 https://doi.org/10.3109/10715769609087998
  44. Wang JF, Komarov P, and de Groot H. Luminol chemiluminescence in rat macrophages and granulocytes: the role of NO, O2-/H2O2, and HOCl. Arch Biochem Biophys 1993; 304: 189-196 https://doi.org/10.1006/abbi.1993.1338
  45. Weitzman SA, and Gordon LI. Inflammation and cancer: role of phagocyte-generated oxidants in carcinogenesis. Blood 1990; 76: 655-663
  46. Xu J, Xu X, and Verstraete W. Adaptation of E. coli cell method for micro-scale nitrate measurement with the Griess reaction in culture media. J Microbiol Methods 2000; 41: 23-33 https://doi.org/10.1016/S0167-7012(00)00141-X
  47. Zhang H, Garlichs CD, Mugge A, and Daniel WG. Involvement of tyrosine kinases, Ca2+ and PKC in activation of mitogen-activated protein (MAP) kinase in human polymorphonuclear neutrophils. J Physiol 1998; 513 ( Pt 2): 359-367 https://doi.org/10.1111/j.1469-7793.1998.359bb.x