Tuberculosis and Respiratory Diseases

The Korean Academy of Tuberculosis and Respiratory Diseases (대한결핵및호흡기학회)
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Growth Inhibition and Apoptosis Induction of Sulindac on Human Lung Cancer Cells

비소세포 폐암 세포주에서 Sulindac의 성장억제와 세포고사 유도

  • Kim, Hak Ryul (Department of Internal Medicne, Wonkwang University College of Medicne) ;
  • Yang, Sei Hoon (Department of Internal Medicne, Wonkwang University College of Medicne) ;
  • Jeong, Eun Taik (Department of Internal Medicne, Wonkwang University College of Medicne)
  • 김학렬 (원광대학교 의과대학 내과학교실) ;
  • 양세훈 (원광대학교 의과대학 내과학교실) ;
  • 정은택 (원광대학교 의과대학 내과학교실)
  • Published : 2004.05.30
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Abstract

Background : Non-steroidal anti-inflammatory drugs (NSAID) are useful in chemoprevention of colorectal cancers. Continuous NSAID administation causes 40% to 50% reduction in relative risk for colorectal cancer. Sulindac possesses an antiproliferative effect and induces apoptosis and tumor regression on colon cancer and other types of cancers. We intended to analyze the effects of sulindac in three non-small cell lung cancer cell lines. Materials and Methods : The human lung cancer cell lines, A549, NCI-H157 and NCI-H460 were used for this study. Viability was tested by MTT assay, and cell death rate was measured by lactate dehydrogenase(LDH) release. Apoptosis was estimated by flow cytometric analysis and nuclear staining. Results: Sulindac was able to decrease the viability of non-small cell lung cancer cells in a dose- and time- dependent manner. In a parallel effect of sulindac on cell death rate, LDH release was increased in sulindac-treated lung cancer cells. Sulindac significantly increased apoptosis characterized by an increase of $sub-G_0/G_1$ fraction and morphological change of nuclei. The rate of apoptotic cells after sulindac treatment in lung cancer cells increased in a time- and dose- dependent manner in flow cytometric analysis. Apoptotic cells were defined as nuclear shrinkage, chromatin condensation and nuclear fragmentation of cells. Conclusion : Sulindac decreases viability and induces the apoptosis of lung cancer cells. Further studies will be needed to elucidate the potential mechanism of sulindac-induced apoptosis in lung cancer cells.

연구 배경 : 비스테로이드성 항염증제는 대장암의 화학 예방에 이용되고 있다. 지속적으로 비스테로이드성 항염증제를 복용한 결과 대장암 발생의 위험이 40-50% 감소하였다. Sulindac은 비스테로이드성 항염증제의 일종으로 대장암의 예방 효과가 있으며 암세포의 성장 억제와 세포 고사를 유도시킨다. 이에 저자들은 3가지 비소세포 폐암 세포주에서 sulindac의 영향을 알아보고자 하였다. 방 법 : A549(선암), NCI-H157(편평상피암), NCI-H460(대세포암) 세포주에 sulindac을 농도별로 투여하여, MTT assay로서 암세포의 생존율을, 유식세포 분석법과 핵산 염색으로 세포 고사의 비율을, 유산탈수소효소유리로서 세포 사멸의 정도를 시간대별로 측정하였다. 결 과 : Sulindac에 의해 농도와 시간에 의존적으로 비소세포 폐암 세포주에서 암세포의 생존율이 감소하였고, 유산 탈수소 효소 유리는 증가하였으며, 세포 고사 역시 농도, 시간에 의존적으로 증가하였다. 결 론 : Sulindac은 비소세포 폐암 세포주에서 농도, 시간에 의존적으로 암세포의 생존율 감소와 세포 고사증가를 유도하였다.

Keywords

References

  1. Rao KV, Detrisac CJ, Steele VE, Hawk ET, Kelloff GJ, McCormick DL. Differential acti-vity of aspirin, ketoprofen and sulindac as cancer chemopreventive agents in the mouse urinary bladder. Carcinogenesis 1996;17:1435-8
  2. Smalley WE, DuBois RN. Colorectal cancer and nonsteroidal anti-inflammatory drugs. Adv Pharmacol 1997;39:1-20
  3. Shiff SJ, Rigas B. Nonsteroidal anti-inflam-matory drugs and colorectal cancer: evolving concepts of their chemopreventive actions Gastroenterology 1997;113:1992-8
  4. Giardiello FM, Spannhake EW, DuBois RN, Hylind LM, Robinson CR, Hubbard WC, et al. Prostaglandin levels in human colorectal mucosa: effects of sulindac in patients with familial adenomatous polyposis. Dig Dis Sci 1998;43:311-6
  5. Giardiello FM, Hamilton SR, Krush AJ, Piantadosi S, Hylind LM, Celano P, et al. Treatment of colonic and rectal adenomas with sulindac in familial adenomatous poly-posis. N Engl J Med 1993;328:1313-6
  6. DuBois RN, Radhika A, Reddy BS, Entingh AJ. Increased cyclo-oxygenase-2 levels in carcinogen-induced rat colonic tumors. Ga-stroenterology 1996;110:1259-62
  7. Piazza GA, Rahm AL, Krutzsch M, Sperl G, Paranka NS, Gross PH, et al. Antineoplastic drugs sulindac sulfide and sulfone inhibit cell growth by inducing apoptosis. Cancer Res 1995;55:3110-6
  8. Han EK, Arber N, Yamamoto H, Lim JT, Delohery T, Pamukcu R, et al. Effects of sulindac and its metabolites on growth and apoptosis in human mammary epithelial and breast carcinoma cell lines. Breast Cancer Res Treat 1998;48:195-203
  9. Soriano AF, Helfrich B, Chan DC, Heasley LE, Bunn PA Jr, Chou TC. Synergistic ef-fects of new chemopreventive agents and conventional cytotoxic agents against human lung cancer cell lines. Cancer Res 1999;59:6178-84
  10. Chan DC, Earle KA, Zhao TL, Helfrich B, Zeng C, Baron A, et al. Exisulind in com bination with docetaxel inhibits growth and metastasis of human lung cancer and pro longs survival in athymic nude rats with orthotopic lung tumors. Clin Cancer Res 2002;8:904-12
  11. Hial V, De Mello MC, Horakova Z, Beaven MA. Antiproliferative activity of anti-inflam matory drugs in two mammalian cell culture lines. J Pharmacol Exp Ther 1977;202:446-54
  12. Waddell WR, Gemer RE. Indomethacin and ascorbate inhibit desmoid tumors. J Surg Oncol 1980;15:85-90
  13. Waddell WR, Loughry R. Sulindac for polyposis of the colon. J Surg Oncol 1983; 24:83-7
  14. Elder DJ, Halton DE, Hague A, Paraskeva C. Induction of apoptotic cell death in human colorectal carcinoma cell lines by a cyclooxy-genase-2 (COX-2)-selective nonsteroidal anti-inflammatory drug: Independence from COX-2 protein expression. Clin Cancer Res 1997;3:1679-83
  15. Lim JT, Piazza GA, Han EK, Delohery TM, Li H, Finn TS, et al. Sulindac derivatives inhibit growth and induce apoptosis in human prostate cancer cell lines. Biochem Pharmacol 1999;58:1097-107
  16. Keller JJ, Offerhaus GJ, Polak M, Goodman SN, Zahurak ML, Hylind LM, et al. Rectal epithelial apoptosis in familial adenomatous polyposis patients treated with sulindac. Gut 1999;45:822-8
  17. Wu YL, Sun B, Zhang XJ, Wang SN, He HY, Qiao MM, et al. Growth inhibition and apoptosis induction of sulindac on human gastric cancer cells. World J Gastroenterol, 2001;7:796-800
  18. Hanif R, Pittas A, Feng Y, Koutsos MI, Qiao L, Staiano-Coico L, et al. Effects of non-steroidal anti-inflammatory drugs on prolifer-ation and on induction of apoptosis in colon cancer cells by a prostaglandin-independent pathway. Biochem Pharmacol 1996;52:237-45
  19. Piazza GA, Rahm AK, Finn TS, Fryer BH, Li H, Stoumen AL, et al. Apoptosis primarily accounts for the growth-inhibitory properties of sulindac metabolites and involves a mechanism that is independent of cyclooxy genase inhibition, cell cycle arrest, and p53 induction. Cancer Res 1997;57:2452-9
  20. Liu JJ, Wang JY, Hertervig E, Nilsson A, Duan RD. Sulindac induces apoptosis, inhibits proliferation and activates caspase-3 in Hep G2 cells. Anticancer Res 2002;22:263-6
  21. Skopinska-Rozewska E, Piazza GA, Sommer E, Pamukcu R, Barcz E, Filewska M, et al. Inhibition of angiogenesis by sulindac and its sulfone metabolite(FGN-1): a potential me-chanism for their antineoplastic properties. Int J Tissue React 1998;20:85-9
  22. Thompson WJ, Pamulku R, Liu L, Li H, Ahnen D, Speri G, et al. Exisulind induced apoptosis in cultured colonic tumor cells involves inhibition of cyclic GMP phospho-diesterase. Proc Am Assoc Cancer Res 1999;40:4-9