Kaohsiung Journal of Medical Sciences
Volume 24, Issue 8 , Pages 392-397, August 2008

Anti-metastatic Action of Non-steroidal Anti-inflammatory Drugs

  • Wen-Chun Hung

      Affiliations

    • Corresponding Author InformationAddress correspondence and reprint requests to: Dr Wen-Chun Hung, Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan

Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan

Received 20 August 2008; accepted 30 August 2008.

Article Outline

Epidemiological studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the incidence and mortality of several types of human cancer. However, the molecular mechanisms by which NSAIDs exert their chemopreventive and anticancer effects are not fully understood. Cyclooxygenase 1 (COX-1) and COX-2 are the main targets for NSAIDs. Recent studies demonstrate that COX-2 is overexpressed in many human cancers and may promote tumorigenesis via: (1) stimulation of cancer cell proliferation; (2) increase of tumor angiogenesis; (3) prevention of cancer cell apoptosis; (4) modulation of immunoregulatory reactions; and (5) enhancement of tumor metastasis. NSAIDs may target the signaling molecules (from upstream activators to downstream effectors) involved in these mechanisms to attenuate the development and progression of cancer. In this review, we discuss the recent findings with regard to the mechanisms by which NSAIDs inhibit tumorigenesis and will specifically focus on the elucidation of NSAID-induced inhibition of tumor metastasis.

Key Words:  cancer , metastasis , nonsteroidal anti-inflammatory drugs , NSAIDs , tumorigenesis

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References 

  1. Waddell WR , Loughry RW . Sulindac for polyposis of the colon . J Surg Oncol . 1983;24:83–87
  2. Thun MJ , Namboodiri MM , Heath CW . Aspirin use and reduced risk of fatal colon cancer . N Engl J Med . 1991;325:1593–1596
  3. Altorki NK , Keresztes RS , Port JL , et al.   Celecoxib, a selective cyclooxygenase-2 inhibitor, enhances the response to preoperative paclitaxel and carboplatin in early-stage non-small-cell lung cancer . J Clin Oncol . 2003;21:2645–2650
  4. Crane CH , Mason K , Janjan NA , et al.   Initial experience combining cyclooxygenase-2 inhibition with chemoradiation for locally advanced pancreatic cancer . Am J Clin Oncol . 2003;26:S81–S84
  5. Konturek PC , Konturek SJ , Bielanski W , et al.   Influence of COX-2 inhibition by rofecoxib on serum and tumor progastrin and gastrin levels and expression of PPARgamma and apoptosis-related proteins in gastric cancer patients . Dig Dis Sci . 2003;48:2005–2017
  6. Pruthi RS , Derksen JE , Moore D . A pilot study of use of the cyclooxygenase-2 inhibitor celecoxib in recurrent prostate cancer after definitive radiation therapy or radical prostatectomy . BJU Int . 2004;93:275–278
  7. Vane JR . Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs . Nat New Biol . 1971;231:232–235
  8. Griswold DE , Adams JL . Constitutive cyclooxygenase (COX-1) and inducible cyclooxygenase (COX-2): rationale for selective inhibition and progress to date . Med Res Rev . 1996;16:181–206
  9. Wu KK . Biochemical pharmacology of nonsteroidal anti-inflammatory drugs . Biochem Pharmacol . 1998;55:543–547
  10. Dubois RN , Abramson SB , Crofford L , et al.   Cyclooxygenase in biology and disease . FASEB J . 1998;12:1063–1073
  11. Simmons DL , Botting RM , Hla T . Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition . Pharmacol Rev . 2004;56:387–437
  12. Eberhart CE , Coffey RJ , Radhika A , et al.   Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas . Gastroenterology . 1994;107:1183–1188
  13. Hwang D , Scollard D , Byrne J , et al.   Expression of cyclooxygenase-1 and cyclooxygenase-2 in human breast cancer . J Natl Cancer Inst . 1998;90:455–460
  14. Okami J , Yamamoto H , Fujiwara Y , et al.   Overexpression of cyclooxygenase-2 in carcinoma of the pancreas . Clin Cancer Res . 1999;5:2018–2024
  15. Tucker ON , Dannenberg AJ , Yang EK , et al.   Cyclooxygenase-2 expression is up-regulated in human pancreatic cancer . Cancer Res . 1999;59:987–990
  16. Hida T , Yatabe Y , Achiwa H , et al.   Increased expression of cyclooxygenase 2 occurs frequently in human lung cancers, specifically in adenocarcinomas . Cancer Res . 1998;58:3761–3764
  17. Cohen EG , Almahmeed T , Du B , et al.   Microsomal prostaglandin E synthase-1 is overexpressed in head and neck squamous cell carcinoma . Clin Cancer Res . 2003;9:3425–3430
  18. Pai R , Soreghan B , Szabo IL , et al.   Prostaglandin E2 transactivates EGF receptor: a novel mechanism for promoting colon cancer growth and gastrointestinal hypertrophy . Nat Med . 2002;8:289–293
  19. Mutoh M , Watanabe K , Kitamura T , et al.   Involvement of prostaglandin E receptor subtype EP(4) in colon carcinogenesis . Cancer Res . 2002;62:28–32
  20. Tsujii M , Kawano S , Tsuji S , et al.   Cyclooxygenase regulates angiogenesis induced by colon cancer cells . Cell . 1998;93:705–716
  21. Gately S . The contributions of cyclooxygenase-2 to tumor angiogenesis . Cancer Metastasis Rev . 2000;19:19–27
  22. Lin MT , Lee RC , Yang PC , et al.   Cyclooxygenase-2 inducing Mcl-1-dependent survival mechanism in human lung adenocarcinoma CL1.0 cells. Involvement of phosphatidylinositol 3-kinase/Akt pathway . J Biol Chem . 2001;276:48997–49002
  23. Sorokin A . Cyclooxygenase-2: potential role in regulation of drug efflux and multidrug resistance phenotype . Curr Pharm Des . 2004;10:647–657
  24. Huang M , Sharma S , Mao JT , et al.   Non-small cell lung cancer-derived soluble mediators and prostaglandin E2 enhance peripheral blood lymphocyte IL-10 transcription and protein production . J Immunol . 1996;157:5512–5520
  25. Dermond O , Ruegg C . Inhibition of tumor angiogenesis by non-steroidal anti-inflammatory drugs: emerging mechanisms and therapeutic perspectives . Drug Resist Updat . 2001;4:314–321
  26. Costa C , Soares R , Reis-Filho JS , et al.   Cyclooxygenase 2 expression is associated with angiogenesis and lymph node metastasis in human breast cancer . J Clin Pathol . 2002;55:429–434
  27. Grosch S , Maier TJ , Schiffmann S , et al.   Cyclooxygenase-2 (COX-2)-independent anticarcinogenic effects of selective COX-2 inhibitors . J Natl Cancer Inst . 2006;98:736–747
  28. Cha YI , DuBois RN . NSAIDs and cancer prevention: targets downstream of COX-2 . Annu Rev Med . 2007;58:239–252
  29. Leahy KM , Koki AT , Masferrer JL . Role of cyclooxygenases in angiogenesis . Curr Med Chem . 2000;7:1163–1170
  30. Rao CV , Reddy BS . NSAIDs and chemoprevention . Curr Cancer Drug Targets . 2004;4:29–42
  31. Kardosh A , Blumenthal M , Wang WJ , et al.   Differential effects of selective COX-2 inhibitors on cell cycle regulation and proliferation of glioblastoma cell lines . Cancer Biol Ther . 2004;3:55–62
  32. Narayanan BA , Condon MS , Bosland MC , et al.   Suppression of N-methyl-N-nitrosourea/testosterone-induced rat prostate cancer growth by celecoxib: effects on cyclooxygenase-2, cell cycle regulation, and apoptosis mechanism(s) . Clin Cancer Res . 2003;9:3503–3513
  33. Grosch S , Tegeder I , Niederberger E , et al.   COX-2 independent induction of cell cycle arrest and apoptosis in colon cancer cells by the selective COX-2 inhibitor celecoxib . FASEB J . 2001;15:2742–2744
  34. Maier TJ , Schilling K , Schmidt R , et al.   Cyclooxygenase-2 (COX-2)-dependent and -independent anticarcinogenic effects of celecoxib in human colon carcinoma cells . Biochem Pharmacol . 2004;67:1469–1478
  35. Hung WC , Chang HC , Pan MR , et al.   Induction of p27(KIP1) as a mechanism underlying NS398-induced growth inhibition in human lung cancer cells . Mol Pharmacol . 2000;58:1398–1403
  36. Huang YC , Chuang LY , Hung WC . Mechanisms under-lying nonsteroidal anti-inflammatory drug-induced p27(Kip1) expression . Mol Pharmacol . 2002;62:1515–1521
  37. Waskewich C , Blumenthal RD , Li H , et al.   Celecoxib exhibits the greatest potency amongst cyclooxygenase (COX) inhibitors for growth inhibition of COX-2-negative hematopoietic and epithelial cell lines . Cancer Res . 2002;62:2029–2033
  38. Nam DH , Park K , Park C , et al.   Intracranial inhibition of glioma cell growth by cyclooxygenase-2 inhibitor celecoxib . Oncol Rep . 2004;11:263–268
  39. Wun T , McKnight H , Tuscano JM . Increased cyclooxygenase-2 (COX-2): a potential role in the pathogenesis of lymphoma . Leuk Res . 2004;28:179–190
  40. Dandekar DS , Lopez M , Carey RI , et al.   Cyclooxygenase-2 inhibitor celecoxib augments chemotherapeutic drug-induced apoptosis by enhancing activation of caspase-3 and -9 in prostate cancer cells . Int J Cancer . 2005;115:484–492
  41. Chang HC , Weng CF . Cyclooxygenase-2 level and culture conditions influence NS398-induced apoptosis and caspase activation in lung cancer cells . Oncol Rep . 2001;8:1321–1325
  42. Jazirehi AR , Bonavida B . Resveratrol modifies the expression of apoptotic regulatory proteins and sensitizes non-Hodgkin's lymphoma and multiple myeloma cell lines to paclitaxel-induced apoptosis . Mol Cancer Ther . 2004;3:71–84
  43. Kern MA , Schubert D , Sahi D , et al.   Proapoptotic and antiproliferative potential of selective cyclooxygenase-2 inhibitors in human liver tumor cells . Hepatology . 2002;36:885–894
  44. Kundu N , Smyth MJ , Samsel L , et al.   Cyclooxygenase inhibitors block cell growth, increase ceramide and inhibit cell cycle . Breast Cancer Res Treat . 2002;76:57–64
  45. Li G , Yang T , Yan J . Cyclooxygenase-2 increased the angiogenic and metastatic potential of tumor cells . Biochem Biophys Res Commun . 2002;299:886–890
  46. Liu XH , Kirschenbaum A , Yao S , et al.   Upregulation of vascular endothelial growth factor by cobalt chloride-simulated hypoxia is mediated by persistent induction of cyclooxygenase-2 in a metastatic human prostate cancer cell line . Clin Exp Metastasis . 1999;17:687–694
  47. Gately S , Li WW . Multiple roles of COX-2 in tumor angiogenesis: a target for antiangiogenic therapy . Semin Oncol . 2004;31:2–11
  48. Ostrowski J , Wocial T , Skurzak H , et al.   Do altering in ornithine decarboxylase activity and gene expression contribute to antiproliferative properties of COX inhibitors? . Br J Cancer . 2003;88:1143–1151
  49. Thyss R , Virolle V , Imbert V , et al.   NF-kappaB/Egr-1/Gadd45 are sequentially activated upon UVB irradiation to mediate epidermal cell death . EMBO J . 2005;24:128–137
  50. Thiel G , Cibelli G . Regulation of life and death by the zinc finger transcription factor Egr-1 . J Cell Physiol . 2002;193:287–292
  51. Stetler-Stevenson WG , Hewitt R , Corcoran M . Matrix metalloproteinases and tumor invasion: from correlation and causality to the clinic . Semin Cancer Biol . 1996;7:147–154
  52. Pupa SM , Ménard S , Forti S , et al.   New insights into the role of extracellular matrix during tumor onset and progression . J Cell Physiol . 2002;192:259–267
  53. Giannelli G , Falk-Marzillier J , Schiraldi O , et al.   Induction of cell migration by matrix metalloprotease-2 cleavage of laminin-5 . Science . 1997;277:225–228
  54. Abiru S , Nakao K , Ichikawa T , et al.   Aspirin and NS-398 inhibit hepatocyte growth factor-induced invasiveness of human hepatoma cells . Hepatology . 2002;35:1117–1124
  55. Pan MR , Hung WC . Nonsteroidal anti-inflammatory drugs inhibit matrix metalloproteinase-2 via suppression of the ERK/Sp1-mediated transcription . J Biol Chem . 2002;277:32775–32780
  56. Pan MR , Chang HC , Hung WC . Non-steroidal anti-inflammatory drugs suppress the ERK signaling pathway via block of Ras/c-Raf interaction and activation of MAP kinase phosphatases . Cell Signal . 2008;20:1134–1141
  57. Banyai L , Patthy L . The NTR module: domains of netrins, secreted frizzled related proteins, and type I procollagen C-proteinase enhancer protein are homologous with tissue inhibitors of metalloproteases . Protein Sci . 1999;8:1636–1642
  58. Egeblad M , Werb Z . New functions for the matrix metalloproteinases in cancer progression . Nat Rev Cancer . 2002;2:161–174
  59. Stetler-Stevenson M , Mansoor A , Lim M , et al.   Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in reactive and neoplastic lymphoid cells . Blood . 1997;89:1708–1715
  60. Takahashi C , Sheng Z , Horan TP , et al.   Regulation of matrix metalloproteinase-9 and inhibition of tumor invasion by the membrane-anchored glycoprotein RECK . Proc Natl Acad Sci USA . 1998;95:13221–13226
  61. Liu LT , Chang HC , Chiang LC , et al.   Induction of RECK by nonsteroidal anti-inflammatory drugs in lung cancer cells . Oncogene . 2002;21:8347–8350
  62. Pan MR , Chang HC , Chuang LY , et al.   The nonsteroidal anti-inflammatory drug NS398 reactivates SPARC expression via promoter demethylation to attenuate invasiveness of lung cancer cells . Exp Biol Med . 2008;233:456–462
  63. Framson PE , Sage EH . SPARC and tumor growth: where the seed meets the soil? . J Cell Biochem . 2004;92:679–690
  64. Moon Y , Bottone FG , McEntee MF , et al.   Suppression of tumor cell invasion by cyclooxygenase inhibitors is mediated by thrombospondin-1 via the early growth response gene Egr-1 . Mol Cancer Ther . 2005;4:1551–1558
  65. Esteller M . Epigenetic gene silencing in cancer: the DNA hypermethylome . Hum Mol Genet . 2007;16:R50–R59

PII: S1607-551X(08)70162-1

doi:10.1016/S1607-551X(08)70162-1

Kaohsiung Journal of Medical Sciences
Volume 24, Issue 8 , Pages 392-397, August 2008

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