Cox-2 (cicloxigenase-2)

Conceito de Cox-2 (cicloxigenase-2)

A cicloxigenase-2, descoberta no inicio da década de noventa1, é uma das isoformas da cicloxigenase, uma enzima que converte o ácido araquidónico em prostaglandinas2 (sendo a outra isoforma a Cox-1) e nos nos humanos é codificada pelo gene PTGS22.

Foi descoberta uma terceira isoforma na espécie canina (Cox-3) sobre a qual existe ainda pouca informação4,5.

Estas enzimas localizam-se na membrana citoplasmática, na superfície luminal do retículo endoplasmático e na membrana nuclear6 e, ao contrário da Cox-1, que é responsável pela produção de prostaglandinas envolvidas na homeostase e expressa na maioria dos tecidos, a Cox-2 está presente em condições fisiológicas apenas nas vesículas seminais7, na placenta, cérebro e rim. É importante salientar que esta isoforma é expressa principalmente em situações patológicas, como reacções inflamatórias e neoplasias8.

Apesar do padrão de expressão diferente, as duas isoformas catalizam a mesma reação7 e possuem sequências quase homólogas, com a exeção da isoleucina 590 do canal do substrato da Cox-1, substituída na Cox-2 por uma valina9, sendo esta diferença a base do desenvolvimento de inibidores seletivos para a Cox-27.

Estas enzimas convertem o ácido araquidónico na prostaglandina H2 (PGH2), através de um processo de dois passos10. Primeiro, o ácido araquidónico é convertido em prostaglandina G2 (PGG2), que em seguida é transformada em PGH2. A PGH2 é a percursora dos vários prostanóides, nos quais será convertida por prostaglandina-sintetases  específicas11 de cada célula/tecido12. Estes prostanóides estão envolvidos em diversos processos biológicos como, por exemplo,  a modulação da resposta imunológica13.

A expressão da Cox-2 pode ser aumentada por diversos fatores , como citoquinas pró-inflamatórias, fatores de crescimento, lipopolissacarídios14, agentes carcinogénicos15, oncogenes16 e agentes oxidativos17. Caso o estímulo cesse, a expressão volta aos valores basais em 24-48 horas (Stack & DuBois, 2001). A expressão desta enzima é inibida por moléculas anti-inflamatórias biológicas, como os corticoesteróides, a IL-13, a IL-10,  IL-418, os anti-oxidantes e a proteína p5315 e os estrogénios19,20.

Existem evidências de sobrexpressão da Cox-2 em diversas neoplasias humanas17, existindo correlação positiva entre esta sobrexpressão e um pior prognóstico21-25. Também nos animais, nomeadamente no cão, cavalo e gato, existem estudos que relatam sobrexpressão da Cox-2 em diversas neoplasias26-44.

Devido ao seu envolvimento em processos neoplásicos, existe grande interesse na utilização de inibidores da Cox-2 na prevenção e tratamento do cancro. Os AINEs são fármacos cujos efeitos benéficos estão associados à inibição da Cox-2, enquanto os seus efeitos secundários estão ligados à inibição da Cox-1. Dentro deste grupo, estão também incluídos os inibidores seletivos da Cox-2 (como o carprofeno). Além destes,  existem também os Coxibs que inibem apenas a Cox-245. No entanto, é importante salientar que os Coxibs possuem efeitos secundários cardio-vasculares46,47.

Apesar dos estudos não serem sempre concordantes48,49, alguns mostram os benefícios da utilização deste tipo de fármacos em diversas neoplasias50-60. Temos o exemplo da Polipose Adenomatosa Familiar (que pode evoluir para para carcinoma colo-retal61 e o sulindac, um AINE que mostrou diminuir a quantidade e o tamanho dos pólipos, induzindo a sua regressão62,63. Outro fármaco, o inibidor seletivo da Cox-2 celecoxib chegou a ser utilizado clinicamente no tratamento da Polipose Adenomatosa Familiar, mas a indicação foi recentemente retirada pela EMEA (European Medicines Agency) e FDA (Food And Drug Administration) por falta de provas da sua eficácia64 e a EMEA concluiu que poderiam existir  riscos relacionados com as elevadas doses  administradas65.

Em 2009 uma revisão de estudos epidemiológicos concluiu que apenas a aspirina pode, de momento, ser utilizada na prevenção de algumas neoplasias, mas que será necessário determinar ainda a dose a administrar, a duração da terapia e a idade de inicio66.

 

Referências:

  1. Simmons D. Cyclooxygenase Isozymes: The Biology of Prostaglandin Synthesis and Inhibition. Pharmacological Reviews. 2004;56(3):387-437.
  2. Stack E, DuBois R. Regulation of cyclo-oxygenase-2. Best Practice & Research Clinical Gastroenterology. 2001;15(5):787-800.
  3. Tay A, Squire J, Goldberg H, Skorecki K. Assignment of the Human Prostaglandin-Endoperoxide Synthase 2 (PTGS2) Gene to 1q25 by Fluorescence in Situ Hybridization. Genomics. 1994;23(3):718-719.
  4. Chandrasekharan N, Dai H, Roos K, Evanson N, Tomsik J, Elton T et al. COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: Cloning, structure, and expression. Proceedings of the National Academy of Sciences. 2002;99(21):13926-13931.
  5. Kis B. Acetaminophen and the Cyclooxygenase-3 Puzzle: Sorting out Facts, Fictions, and Uncertainties. Journal of Pharmacology and Experimental Therapeutics. 2005;315(1):1-7.
  6. Claria Cyclooxygenase-2 Biology. Current Pharmaceutical Design. 2003;9(27):2177-2190.
  7. Zha S, Yegnasubramanian V, Nelson W, Isaacs W, De Marzo A. Cyclooxygenases in cancer: progress and perspective. Cancer Letters. 2004;215(1):1-20.
  8. Doré M. Cyclooxygenase-2 Expression in Animal Cancers. Veterinary Pathology. 2010;48(1):254-265.
  9. Kurumbail R, Stevens A, Gierse J, McDonald J, Stegeman R, Pak J et al. Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Nature. 1996;384(6610):644-648.
  10. Eberhart C, Dubois R. Eicosanoids and the gastrointestinal tract. Gastroenterology. 1995;109(1):285-301.
  11. Smith WL, DeWitt DL, Garavito RM. Cyclooxygenases: structural, cellular, and molecular biology. Annual Review of Biochemistry. 2000;69: 145-182.
  12. Schafer A. Effects of Nonsteroidal Antiinflammatory Drugs on Platelet Function and Systemic Hemostasis. The Journal of Clinical Pharmacology. 1995;35(3):209-219.
  13. Stack E, DuBois R. Regulation of cyclo-oxygenase-2. Best Practice & Research Clinical Gastroenterology. 2001;15(5):787-800.
  14. Dubois RN, Abramson SB, Crofford L, Gupta RA, Simon LS, Van De Putte LB,  Lipsky PE. Cyclooxygenase in biology and disease. FASEB journal: official publication of the Federation of American Societies for Experimental Biology. 1998;12(12), 1063-1073.
  15. Fosslien E. Biochemistry of Cyclooxygenase (COX)-2 Inhibitors and Molecular Pathology of COX-2 in Neoplasia. Critical Reviews in Clinical Laboratory Sciences. 2000;37(5):431-502.
  16. Subbaramaiah K, Telang N, Ramonetti JT, Araki R, DeVito B, Weksler BB, Dannenberg AJ. Transcription of cyclooxygenase-2 is enhanced in transformed mammary epithelial cells. Cancer Research. 1996;56(19), 4424-4429.
  17. Divvela AKC, Challa SR, Tagaram IK. Pathogenic Role of Cyclooxygenase-2 in Cancer. Journal of Health Science. 2010;56(5), 502-516.
  18. Niiro H, Otsuka T, Ogami E, Yamaoka K, Nagano S, Akahoshi M, Nakashima H, Arinobu Y, Izuhara K, Niho Y. MAP kinase pathways as a route for regulatory mechanisms of IL- 10 and IL-4 which inhibit Cox-2 expression in human monocytes. Biochemical and Biophysical Research Communications. 1998;250(2), 200-205.
  19. Ospina JA, Brevig HN, Krause DN, Duckles SP. Estrogen suppresses IL-1betamediated induction of Cox-2 pathway in rat cerebral blood vessels. American Journal of Physiology – Heart and Circulatory Physiology. 2003;286(5), H2010-2019.
  20. Martínez SP, Hermoso M, Farina M, Ribeiro ML, Rapanelli M, Espinosa M, Villalón M, Franchi A. 17-beta-Estradiol upregulates Cox-2 in the rat oviduct. Prostaglandins & Other Lipid Mediators. 2006;80(3-4), 155-164.
  21. Becker M, Siegelin M, Rompel R, Enk A, Gaiser T. COX-2 expression in malignant melanoma: a novel prognostic marker?. Melanoma Research. 2009;19(1):8-16.
  22. Gallo O, Masini E, Bianchi B, Bruschini L, Paglierani M, Franchi A. Prognostic significance of cyclooxygenase-2 pathway and angiogenesis in head and neck squamous cell carcinoma. Human Pathology. 2002;33(7):708-714.
  23. Khor L, Bae K, Pollack A, Hammond M, Grignon D, Venkatesan V et al. COX-2 expression predicts prostate-cancer outcome: analysis of data from the RTOG 92-02 trial. The Lancet Oncology. 2007;8(10):912-920.
  24. Shono T, Tofilon PJ, Bruner JM, Owolabi O, Lang FF. Cyclooxygenase-2 expression in human gliomas: prognostic significance and molecular correlations. Cancer Research. 2001;61(11), 4375-4381.
  25. Cetin M, Buyukberber S, Demir M, Sari I, Sari I, Deniz K et al. Overexpression of cyclooxygenase-2 in multiple myeloma: Association with reduced survival. American Journal of Hematology. 2005;80(3):169-173.
  26. de Almeida E, Piche C, Sirois J, Dore M. Expression of Cyclo-oxygenase-2 in Naturally Occurring Squamous Cell Carcinomas in Dogs. Journal of Histochemistry & Cytochemistry. 2001;49(7):867-875.
  27. Khan K, Knapp D, Denicola D, Harris R. Expression of cyclooxygenase-2 in transitional cell carcinoma of the urinary bladder in dogs. American Journal of Veterinary Research. 2000;61(5):478-481.
  28. Borzacchiello G, Paciello O, Papparella S. Expression of Cyclooxygenase-1 and -2 in Canine Nasal Carcinomas. Journal of Comparative Pathology. 2004;131(1):70-76.
  29. Mcentee M, Cates J, Neilsen N. Cyclooxygenase-2 Expression in Spontaneous Intestinal Neoplasia of Domestic Dogs. Veterinary Pathology. 2002;39(4):428-436.
  30. Borzacchiello G, Russo V, Russo M. Immunohistochemical Expression of Cyclooxygenase-2 in Canine Ovarian Carcinomas. Journal of Veterinary Medicine Series A. 2007;54(5):247-249.
  31. Mohammed S, Khan K, Sellers R, Hayek M, DeNicola D, Wu L et al. Expression of cyclooxygenase-1 and 2 in naturally-occurring canine cancer. Prostaglandins, Leukotrienes and Essential Fatty Acids. 2004;70(5):479-483.
  32. Mullins M, Lana S, Dernell W, Ogilvie G, Withrow S, Ehrhart E. Cyclooxygenase-2 Expression in Canine Appendicular Osteosarcomas. Journal of Veterinary Internal Medicine. 2004;18(6):859-865.
  33. Doré M, Lanthier I, & Sirois J. Cyclooxygenase-2 expression in canine mammary tumors. Veterinary Pathology. 2003;40(2), 207-212.
  34. Queiroga FL, Alves A, Pires I, Lopes C. Expression of Cox-1 and Cox-2 in caninemammary tumours. Journal of Comparative Pathology. 2007;136(2-3), 177-185.
  35. Pereira PD, Lopes CC, Matos AJ, Santos M, Gärtner F, Medeiros R, Lopes C. Cox-2expression in canine normal and neoplastic mammary gland. Journal of Comparative Pathology. 2009;140(4), 247-253.
  36. Elce YA, Orsini JA, Blikslager AT. Expression of cyclooxygenase-1 and -2 in naturally occurring squamous cell carcinomas in horses. American Journal of Veterinary Research. 2007; 68(1), 76-80.
  37. Beam SL, Rassnick KM, Moore AS,  McDonough SP. An immunohistochemical study of cyclooxygenase-2 expression in various feline neoplasms. Veterinary Pathology. 2003;40(5), 496-500.
  38. Hayes A, Scase T, Miller J, Murphy S, Sparkes A, Adams V. Cox-1 and Cox-2 expression in feline oral squamous cell carcinoma. Journal of Comparative Pathology. 2006;135(2-3), 93-99.
  39. DiBernardi L, Doré M, Davis JA, Owens JG, Mohammed SI, Guptill CF, Knapp DW. Study of feline oral squamous cell carcinoma: potential target for cyclooxygenase inhibitor treatment. Prostaglandins, Leukotrienes and Essential Fatty Acids. 2007;76(4), 245-250.
  40. Newman, S.J. & Mrkonjich, L. (2006). Cyclooxygenase-2 expression in feline pancreatic adenocarcinomas. Journal of Veterinary Diagnostic Investigation, 18(6), 590-593.
  41. Costa RMG, Santos M, Amorim I, Lopes C, Pereira PD, Faustino AM. An immunohistochemical study of feline endometrial adenocarcinoma. Journal of Comparative Pathology. 2009;140(4), 254-259.
  42. Bardagí M, Fondevila D. Ferrer, L. Immunohistochemical detection of Cox-2 in feline and canine actinic keratoses and cutaneous squamous cell carcinoma. Journal of Comparative Pathology. 2012;146(1), 11-17.
  43. Millanta F, Citi S, Della Santa D, Porciani M. Poli A. Cox-2 expression in canine and feline invasive mammary carcinomas: correlation with clinicopathological features and prognostic molecular markers. Breast Cancer Research and Treatment. 2006;98(1), 115-210.
  44. Sayasith K, Sirois J. Doré M. Molecular characterization of feline Cox-2 and expression in feline mammary carcinomas. Veterinary Pathology. 2009;46(3), 423-429.
  45. Hayes A. Cancer, cyclo-oxygenase and nonsteroidal anti-inflammatory drugs – can we combine all three? Veterinary and Comparative Oncology. 2007;5(1), 1-13.
  46. Bertagnolli M, Eagle C, Zauber A, Redston M, Solomon S, Kim K et al. Celecoxib for the Prevention of Sporadic Colorectal Adenomas. New England Journal of Medicine. 2006;355(9):873-884.
  47. Bresalier R, Sandler R, Quan J. Cardiovascular Events Associated With Rofecoxib in a Colorectal Adenoma Chemoprevention Trial. ACC Current Journal Review. 2005;14(6):5.
  48. Cook N, Lee I, Gaziano J. Low-Dose Aspirin in the Primary Prevention of Cancer. The Women’s Health Study: A Randomized Controlled Trial. ACC Current Journal Review. 2005;14(10):11-12.
  49. Giovannucci E, Egan KM, Hunter DJ, Stampfer MJ, Colditz GA, Willett WC.  Speizer, F.E. Aspirin and the risk of colorectal cancer in women. New England Journal of Medicine. 1995;333(10), 609-614.
  50. Farrow DC, Vaughan TL, Hansten PD, Stanford JL, Risch HA, Gammon MD, Chow WH, Dubrow R, Ahsan H, Mayne ST, Schoenberg JB, West AB, Rotterdam H, Fraumeni JF. Blot WJ. Use of aspirin and other nonsteroidal anti-inflammatory drugs and risk of esophageal and gastric cancer. Cancer Epidemiology Biomarkers and Prevention. 1998;7(2), 97-102.
  51. Thun M, Namboodiri M, Heath C. Aspirin Use and Reduced Risk of Fatal Colon Cancer. New England Journal of Medicine. 1991;325(23):1593-1596.
  52. García Rodríguez L, Huerta-Alvarez C. Reduced Risk of Colorectal Cancer among Long-Term Users of Aspirin and Nonaspirin Nonsteroidal Antiinflammatory Drugs. Epidemiology. 2001;12(1):88-93.
  53. Flossmann E, Rothwell P. Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies. The Lancet. 2007;369(9573):1603-1613.
  54. Sharpe CR, Collet JP, McNutt M, Belzile E, Boivin JF. Hanley JA. Nested casecontrol study of the effects of non-steroidal anti-inflammatory drugs on breast cancer risk and stage. British Journal of Cancer. 2000;83(1), 112-120.
  55. Holmes M, Chen W, Li L, Hertzmark E, Spiegelman D, Hankinson S. Aspirin Intake and Survival After Breast Cancer. Journal of Clinical Oncology. 2010;28(9):1467-1472.
  56. Harris RE, Beebe-Donk J. Alshafie GA. Reduction in the risk of human breast cancer by selective cyclooxygenase-2 (Cox-2) inhibitors. BMC Cancer. 2006;6, 27.
  57. Rothwell P, Fowkes F, Belch J, Ogawa H, Warlow C, Meade T. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. The Lancet. 2011;377(9759):31-41.
  58. Castelao JE, Yuan JM, Gago-Dominguez M, Yu MC. Ross, RK. Non-steroidal antiinflammatory drugs and bladder cancer prevention. British Journal of Cancer. 2000;82(7), 1364-1369.
  59. Norrish A, Jackson R, McRae C. Non-steroidal anti-inflammatory drugs and prostate cancer progression. International Journal of Cancer. 1998;77(4):511-515.
  60. Valsecchi M, Pomerantz S, Jaslow R, Tester W. Reduced Risk of Bone Metastasis for Patients With Breast Cancer Who Use COX-2 Inhibitors. Clinical Breast Cancer. 2009;9(4):225-230.
  61. Hayes A. Cancer, cyclo-oxygenase and nonsteroidal anti-inflammatory drugs ? can we combine all three?. Veterinary and Comparative Oncology. 2007;5(1):1-13.
  62. Giardiello F, Offerhaus J, Tersmette A, Hylind L, Krush A, Brensinger J et al. Sulindac induced regression of colorectal adenomas in familial adenomatous polyposis: evaluation of predictive factors. Gut. 1996;38(4):578-581.
  63. Tonelli F, Valanzano R, Messerini L, Ficari F. Long-term treatment with sulindac in familial adenomatous polyposis: Is there an actual efficacy in prevention of rectal cancer?. Journal of Surgical Oncology. 2000;74(1):15-20.
  64. European Medicines Agency (2010). Questions and answers on the potential off-label use of celecoxib in patients with familial adenomatous polyposis. Londres: EMA. Acedido em mar. 7, 2015. Disponível em: http://www.emea.europa.eu/docs/en_GB/document_library/Medicine_QA/2011/05/WC500106538.pdf
  65. Food and Drug Administration (2012, junho 8). Pfizer, Inc; Withdrawal of Approval of Familial Adenomatous Polyposis Indication for CELEBREX. Federal Register, 77(111).
  66. Cuzick J, Otto F, Baron J, Brown P, Burn J, Greenwald P et al. Aspirin and non-steroidal anti-inflammatory drugs for cancer prevention: an international consensus statement. The Lancet Oncology. 2009;10(5):501-507.
2030 Visualizações 1 Total
2030 Visualizações

 

 

Knoow - a divulgar conhecimento pelo mundo

Flag Counter