Radiation Oncology Journal

  • 제21권3호
  • /
  • Pages.216-221
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  • 2003
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  • 2234-1900(pISSN)
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  • 2234-3156(eISSN)
대한방사선종양학회 (The Korean Society for Radiation Oncology)
권호 표지

선택적 Cyclooxygenase-2 억제제인 Celecoxib가 상이한 Cyclooxygenase-2 발현량을 가진 인간 암세포주들에 대하여 유도하는 방사선 감수성 증진 작용

The Enhancement of Radiosensitivity by Celecoxib, Selective Cyclooxygenase-2 Inhibitor, on Human Cancer Cells Expressing Differential Levels of Cyclooxygenase-2

  • 표홍렬 (국립암센터 호발암연구부 폐암연구과) ;
  • 신유근 (연세대학교 암전이연구센터) ;
  • 김현석 (연세대학교 두뇌한국21 의과학사업단, 연세암센터) ;
  • 성진실 (연세대학교 의과대학 방사선종양학교실, 연세암센터) ;
  • 서창옥 (연세대학교 의과대학 방사선종양학교실, 연세암센터) ;
  • 김귀언 (연세대학교 의과대학 방사선종양학교실, 연세암센터)
  • Pyo Hongryull (Lung Cancer Branch, Division of Common Cancer, National Cancer Center) ;
  • Shin You Keun (Yonsei University, Cancer Metastasis Research Center,) ;
  • Kim Hyun Seok (Yonsei University Brain Korea 21 Project for Medical Science, Yonsei Cancer Center) ;
  • Seong Jinsil (Yonsei University Department of Radiation Oncology, College of Medicine, Yonsei Cancer Center) ;
  • Suh Chang Ok (Yonsei University Department of Radiation Oncology, College of Medicine, Yonsei Cancer Center) ;
  • Kim Gwi Eon (Yonsei University Department of Radiation Oncology, College of Medicine, Yonsei Cancer Center)
  • 발행 : 2003.09.01
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초록

목적: Cyclooxygenase-2 (COX-2)를 과발현하는 A549 인간폐암세포주와 발현하지 않는 MCF-7 인간유방암세포주에서 선택적 COX-2 억제제인 celecoxib의 방사선 감수성 증진 작용을 관찰하고자 하였다. 대상 및 방법: A549 세포와 MCF-7 세포에 대해서 방사선 혹은 방사선과 celecoxib를 병용 투여한 후에 clonogenic radiation survival 실험을 시행하였다. 같은 실험을 각각 $10\%$와 $1\%$의 FBS를 포함한 배지에서 반복하였다. 각 세포에 방사선과 celecoxib를 동시 혹은 단독 투여한 후에 각 실험 그룹의 세포사멸을 측정하였다. 결과: 약물 투여 기간 동안 $10\%$의 혈청을 포함한 배지 조건에서 배양된 A549세포에서는, $30\muM$과 $50\muM$ 농도의 celecoxib가 투여된 상태에서 surviving fraction=0.1에서의 Radiation enhancement ratio (RER)가 각각 1.58과 1.81로 celecoxib가 A549 세포의 방사선 감수성을 증가시켰다. 이러한 방사선 감수성의 증가는 세포를 $1\%$의 혈청을 포함한 배지에서 배양하였을때는 소실되었다. MCF-7 세포에서는 $10\%$와 $1\%$ 혈청을 포함한 각각의 배지조건 하에서celecoxib에 의한 방사선 감수성의 변화가 관찰되지 않았다. A549와 MCF-7 세포의 각 그룹에서 세포사멸을 측정한 결과 celecoxib와 방사선이 병용 투여되었을 때 유도되는 세포사멸은 상호 상승적이지 않은 것으로 나타났다. 결론: COX-2 선택적 억제제인 celecoxib는 COX-2를 과발현하는 A549 세포에서 선택적으로 방사선 감수성을 증진시켰으며, 저농도의 혈청을 포함한 배지 조건에서는 이러한 효과가 소실되었다. COX-2를 발현하지 않는 MCF-7 세포주에서는 celecoxib에 의해서 방사선 감수성이 변화되지 않았으며, 이러한 celecoxib의 방사선 감수성 증진 작용 기전에 세포 사멸은 관여하지 않는 것으로 보인다.

Purpose: To investigate the modulation of radiosensitivity by celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, on cancer cells over- and under-expressing COX-2. Materials and Methods: A clonogenic radiation survival analysis was performed on A549 human lung and MCF-7 human breast cancer cell lines incubated in both 1 and $10\%$ fetal bovine serum (FBS) containing media. The apoptosis in both cell lines was measured after treatment with radiation and/or celecoxib. Results: Celecoxib enhanced the radiation sensitivity of the A549 cells in the medium containing the $10\%$ FBS, with radiation enhancement ratios of 1.58 and 1.81 respectively, at surviving fractions of 0.1, with $30\muM\;and\;50\muM$ celecoxib. This enhanced radiosensitivity disappeared in the medium containing the $1\%$ FBS. Celecoxib did not change the radiation sensitivity of the MCF-7 cells in either media. The induction of apoptosis by celecoxib and radiation was not synergistic in either cell line. Conclwsion: Celecoxib, a selective COX-2 inhibitor, preferentially enhanced the effect of radiation on COX-2 over-expressing cancer cells compared to the cells with a low expression, and this effect disappeared on incubation of the cells during drug treatment in the medium with suboptimal serum concentration. Apoptosis did not appear to be the underlying mechanism of this radiation enhancement effect due to celecoxib on the A549 cells. These findings suggest radiosensitization by a selective COX-2 inhibitor is COX-2 dependent.

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참고문헌

  1. Herschman HR. Primary response genes induced by growth factors and tumor promoters.AnnuRevBiochem 1991;60: 281-319 https://doi.org/10.1146/annurev.bi.60.070191.001433
  2. WilliamsCS,MannM,DuBoisRN. Theroleofcyclooxy genases in inflammation, cancer, and development. Oncogene 1999;18:7908-7916 https://doi.org/10.1038/sj.onc.1203286
  3. TuckerON,Dannenberg AJ, Yang EK, et al. Cyclooxygenase-2 expression is up-regulated in human pancreatic cancer. Cancer Res 1999;59:987-990
  4. Uefuji K, Ichikura T, Mochizuki H, Shinomiya N. Expression of cyclooxygenase-2 protein in gastric adenocarcinoma. J Surg Oncol 1998;69:168-172 https://doi.org/10.1002/(SICI)1096-9098(199811)69:3<168::AID-JSO9>3.0.CO;2-0
  5. Sano H, Kawahito Y, Wilder RL, et al. Expression of cyclooxygenase-1 and 2 in human colorectal cancer. Cacner Res 1995;55:3785-3789
  6. Battu S,Rigaud M, Beneytout JL. Resistance to apoptosis and cyclooxygenase-2 expression in a human adenocarcinoma celllineHT29CL.19A.AnticancerRes1998;18:3579-3583
  7. ChanG.BoyleJO,YangEK,etal. Cyclooxygenase-2expression is up-regulated in squamous cell carcinoma of the head and neck. Cancer Res 1999;59:991-994
  8. Elder DJE, Halton DE, Hague A, Paraskeva C. Induction of apoptotic cell death in human colorectal carcinoma cell lines by a cyclooxygenase-2 (COX-2)- selective nonsteroidal anti-inflammatory drug: independence from COX-2 protein expression. Clin Cancer Res 1997;3:1679-1683
  9. Hida T, Yatabe Y, Achiwa H, et al. Increased expression of cyclooxygenase 2 occurs frequently in human lung cancers,specifically in adenocarcinomas.CancerRes1998; 58:3761-3764
  10. Milas L, Kishi K, Hunter N, Mason K, Masferrer JL, Tofilon PJ. Enhancement of tumor response to -radiation by an inhibitor of cyclooxygenase-2 enzyme. J Natl Cancer Inst 1999;91:1501-1504 https://doi.org/10.1093/jnci/91.17.1501
  11. Taketo MM. Cyclooxygenase-2 inhibitors in tumorigenesis (part II). J Natl Cancer Inst 1998;90:1609-1620 https://doi.org/10.1093/jnci/90.21.1609
  12. Rioux N, Castonguay A. Prevention of NNK-induced lung tumorigenesis in A/J mice by acetylsalicylic acid and NS- 398. Cancer Res 1998;58:5354-5360
  13. Kalgutkar AS, Crews BC, Rowlinson SW, Garner C, Seibert K, MarnettLJ. Aspirin-like moleculesthatcovalently inactivate cyclooxygenase-2. Science 1998;280:1268- 1270 https://doi.org/10.1126/science.280.5367.1268
  14. CrewTE,ElderDJE,Paraskeva CA. Cyclooxygenase-2(COX-2) selective non-steroidal anti-inflammatory drug enhances the growth inhibitory effect of butyrate in colorectal carcinoma cells expressing COX-2 protein: regulation of COX-2 by butyrate. Carcinogenesis 2000;21:69-77 https://doi.org/10.1093/carcin/21.1.69
  15. Hsu AL, Ching TT,WangDS,SongX,RangnekarVM, Chen CS. The cyclooxygenase-2 inhibitorCelecoxib induces apoptosis by blocking Akt activation in human prostate cancer cells independentlyofBcl- 2.JBiolChem2000;275: 11397-11403
  16. LiuXH,YaoS,KirschenbaumA,LevineAC. NS398, a selective cyclooxygenase-2 inhibitor, induces apoptosis and down-regulates bcl-2 expression in LNCaP cells. Cancer Res 1998;58:4245-4249
  17. Hara A, Yoshimi N, Niwa M, Ino N, Mori H. Apoptosis induced by NS-398, a selective cyclooxygenase-2 inhibitor, in human colorectal cancer cell lines. Jpn J. Cancer Res 1997;88:600-604
  18. Sheng H, ShaoJ,KirklandSC,etal. Inhibitionofhumancolon cancer cell growth by selective inhibition of cyclooxygenase- 2. J Clin Invest 1997;99:2254-2259 https://doi.org/10.1172/JCI119400
  19. Sheng H, Shao J, Morrow JD, Beauchamp RD, DuBois RN. Modulation of apoptosis and Bcl-2 expression by prostaglandin E$_2$ in human colon cancer cells. Cancer Res 1998; 58:362-366
  20. MilasL,FurutaY,HunterN,NishiguchiI,RunkelS. Dependence of indomethacin-induced potentiation of murine tumor radioresponse on tumor host immunocompetence. Cancer Res 1990;50:4473-4477
  21. Palayoor ST, Bump EA, Calderwood SK, Bartol S, Coleman CN. Combined antitumor effect of radiation and ibuprofen in human prostate carcinoma cells. Clin Cancer Res 1998;4:763-771
  22. Furuta Y, Hunter N, Barkley T Jr, Hall E, Milas L. Increase in radioresponse of murine tumors by treatment with indomethacin. Cancer Res 1988;48:3008-3013
  23. Kishi K, Petersen S, Petersen C, et al. Preferential enhancement of tumor radioresponse by a cyclooxygenase- 2 inhibitor. CancerRes2000;60:1326-1331
  24. Petersen C, Petersen S, Milas L, Lang FF, Tofilon PJ. Enhancement of intrinsic tumor cell radiosensitivity induced by a selective cyclooxygenase-2 inhibitor. Clin Cancer Res 2000;6:2513-2520
  25. Pyo H, Choy H, Amorino GP, et al. A selective cyclooxygenase- 2 inhibitor, NS-398, enhances the effect of radiation in vitro and in vivo preferentially on the cells which express cyclooxygenase-2. Clin Cancer Res 2001;7:2998-3005
  26. DuBois RN, Shao J, Tsujii M, Sheng H, BeauchampRD. G1 delay in cells overexpressing prostaglandin endoperoxide synthase-2. Cancer Res 1996;56: 733-737
  27. Toyoshima T, Kamijo R, Takizawa K, SumitaniK,ItoD,Nagumo M. Inhibitor of cyclooxygenase-2 induces cell-cyclearrest in the epithelial cancer celllineviaup-regulation of cyclin dependent kinase inhibitor p21. Br J Cancer 2002; 86:1150-1156 https://doi.org/10.1038/sj.bjc.6600183
  28. Furuta Y, Hall ER, Sanduja S, Barkley T Jr, Milas L. Prostaglandin production by murine tumors as a predictor for therapeutic response to indomethacin. Cancer Res 1988;48: 3002-3007
  29. Gilroy D, Saunders M,WuK.COX-2expressionandcell cycleprogressioninhumanfibroblasts.AmJPhysiolCellPhysiol 2001;281:C188-C194
  30. Gilroy D, Saunders M, Sansores-Garcia L, Matijevic- Aleksic N, Wu K. Cell cycle-dependent expression of cyclooxygenase-2 in human fibroblasts. FASEB J 2001;15: 288-90 https://doi.org/10.1096/fj.00-0573fje
  31. Eric J Hall. Repairof radiation damage andthedose-rate effect. In: Eric J Hall, eds. Radiobiology for the radiobiologist. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins Co. 2000:67-90
  32. ChangH,WengC.Cyclooxygenase-2 level andcultureconditions influence NS398-induced apoptosis and caspase ctivation in lung cancer cells. Oncol Rep 2001;8:1321-1325