생명과학회지 (Journal of Life Science)

  • 제23권5호
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  • Pages.622-628
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  • 2013
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  • 1225-9918(pISSN)
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  • 2287-3406(eISSN)
한국생명과학회 (Korean Society of Life Science)
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U937 인체혈구암세포에서 diallyl trisulfide에 의한 mitotic arrest와 apoptosis 유발

Induction of Mitotic Arrest and Apoptosis by Diallyl Trisulfide in U937 Human Leukemia Cells

  • 박현수 (부산대학교 한의학전문대학원) ;
  • 이준혁 (특허청 화학생명공학심사국 생명공학심사과) ;
  • 손병일 (동의대학교 Blue-Bio 소재 개발 및 실용화 지원 센터) ;
  • 최병태 (부산대학교 한의학전문대학원) ;
  • 최영현 (동의대학교 항노화연구소)
  • Park, Hyun Soo (School of Korean Medicine, Busan National University) ;
  • Lee, Jun Hyuk (Biotechnology Examination Division, Chemistry and Biotechnology Examination Bureau, Korean Intellectual Property Office) ;
  • Son, Byoung Yil (Blue-Bio Industry Regional Innovation Center & Dongeui University) ;
  • Choi, Byung Tae (School of Korean Medicine, Busan National University) ;
  • Choi, Yung Hyun (Anti-Aging Research Center & Dongeui University)
  • 투고 : 2013.03.07
  • 심사 : 2013.03.22
  • 발행 : 2013.05.30
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초록

본 연구에서는 마늘에서 유래된 생리활성 물질인 diallyl trisulfide (DATS) 처리에 따른 U937 인체혈구암세포의 증식억제가 apoptosis 및 cell cycle arrest 유발과 관련이 있는지 조사하였다. U937 세포증식은 DATS에 의해 농도 및 시간 의존적으로 감소함을 확인 하였고, 이는 apoptosis에 의한 직접적인 세포죽음과 CDK1 및 cyclin B1의 발현 증가 및 histone H3의 인산화와 연관된 mitotic arrest와 관련이 있음을 알 수 있었다. 또한 DATS 처리 초기에 reactive oxygen species (ROS)의 생성이 매우 증가되었으나, ROS scavenger (N-acetyl-l-cysteine)에 의한 인위적 ROS 생성의 억제는 DATS에 의한 apoptosis 및 mitotic arrest를 완벽하게 차단시켰다. 이는 U937 세포에서 DATS에 의해 유도된 apoptosis 및 mitotic arrest가 ROS에 의해 매개된다는 것을 의미하며, 본 연구의 결과는 DATS가 인체혈구암세포에서 세포증식억제와 관련된 항암기전을 이해할 수 있는 기초자료로서 매우 유용하게 사용될 것이라 생각된다.

Diallyl trisulfide (DATS), one of the major organosulfur components of garlic (Allium sativum), has various biological effects such as anti-microbial and anti-cancer activities. However, the molecular mechanisms of growth inhibition related to cell cycle arrest are poorly understood. In this study, we investigated the effects of DATS on cell cycle progression in U937 human leukemia cells. Treatment with DATS in U937 cells resulted in inhibition of cell viability through G2/M arrest and apoptosis. DATS-induced G2/M arrest was associated with up-regulation of cyclin B1 and cyclin-dependent kinase 1 (CDK1). DATS also significantly increased levels of phospho-histone H3, which is a mitosis-specific marker, indicating that DATS induced mitotic arrest but not G2 arrest in U937 cells. DATS treatment also generated the reactive oxygen species (ROS) in U937 cells; however, pretreatment with N-acetyl-l-cysteine (NAC), a ROS scavenger, significantly attenuated DATS-induced mitotic arrest and apoptosis. Taken together, our data indicate that DATS exhibits anti-cancer effects through mitotic arrest and apoptosis in a ROS-dependent manner.

키워드

참고문헌

  1. Abramson, N. and Melton, B. 2000. Leukocytosis: basics of clinical assessment. Am Fam Physician 62, 2053-2060.
  2. Barzilai, A. and Yamamoto, K. 2004. DNA damage responses to oxidative stress. DNA Repair (Amst) 3, 1109-1115. https://doi.org/10.1016/j.dnarep.2004.03.002
  3. Blagosklonny, M. V. 2007. Mitotic arrest and cell fate: why and how mitotic inhibition of transcription drives mutually exclusive events. Cell Cycle 6, 70-74. https://doi.org/10.4161/cc.6.1.3682
  4. Chen, M., Li, B., Zhao, X., Zuo, H., He, X., Li, Z., Liu, X. and Chen, L. 2012. Effect of diallyl trisulfide derivatives on the induction of apoptosis in human prostate cancer PC-3 cells. Mol Cell Biochem 363, 75-84. https://doi.org/10.1007/s11010-011-1159-9
  5. Choi, Y. H. and Park, H. S. 2012. Apoptosis induction of U937 human leukemia cells by diallyl trisulfide induces through generation of reactive oxygen species. J Biomed Sci 19, 50. https://doi.org/10.1186/1423-0127-19-50
  6. Cline, M. J. 1994. The molecular basis of leukemia. N Engl J Med 330, 328-336. https://doi.org/10.1056/NEJM199402033300507
  7. D'Autreaux, B. and Toledano, M. B. 2007. ROS as signalling molecules: mechanisms that generate specificity in ROS homeostasis. Nat Rev Mol Cell Biol 8, 813-824. https://doi.org/10.1038/nrm2256
  8. Dalton, W. B., Nandan, M. O., Moore, R. T. and Yang, V. W. 2007. Human cancer cells commonly acquire DNA damage during mitotic arrest. Cancer Res 67, 11487-11492. https://doi.org/10.1158/0008-5472.CAN-07-5162
  9. Elmore, S. 2007. Apoptosis: a review of programmed cell death. Toxicol Pathol 35, 495-516. https://doi.org/10.1080/01926230701320337
  10. Gayathri, R., Gunadharini, D. N., Arunkumar, A., Senthilkumar, K., Krishnamoorthy, G., Banudevi, S., Vignesh, R. C. and Arunakaran, J. 2009. Effects of diallyl disulfide (DADS) on expression of apoptosis associated proteins in androgen independent human prostate cancer cells (PC-3). Mol Cell Biochem 320, 197-203. https://doi.org/10.1007/s11010-008-9903-5
  11. Gilliland, D. G., Jordan, C. T. and Felix, C. A. 2004. The molecular basis of leukemia. Hematology Am Soc Hematol Educ Program 2004, 80-97. https://doi.org/10.1182/asheducation-2004.1.80
  12. Hseu, Y. C., Lee, M. S., Wu, C. R., Cho, H. J., Lin, K. Y., Lai, G. H., Wang, S. Y., Kuo, Y. H., Kumar, K. J. and Yang, H. L. 2012. The chalcone flavokawain B induces G2/M cell-cycle arrest and apoptosis in human oral carcinoma HSC-3 cells through the intracellular ROS generation and downregulation of the Akt/p38 MAPK signaling pathway. J Agric Food Chem 60, 2385-2397. https://doi.org/10.1021/jf205053r
  13. Liu, K. L., Chen, H. W., Wang, R. Y., Lei, Y. P., Sheen, L. Y. and Lii, C. K. 2006. DATS reduces LPS-induced iNOS expression, NO production, oxidative stress, and NF-kappaB activation in RAW 264.7 macrophages. J Agric Food Chem 54, 3472-3478. https://doi.org/10.1021/jf060043k
  14. Malumbres, M and Barbacid, M. 2009. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer 9, 153-166. https://doi.org/10.1038/nrc2602
  15. Mates, J. M., Segura, J. A., Alonso, F. J. and Marquez, J. 2012. Oxidative stress in apoptosis and cancer: an update. Arch Toxicol 86, 1649-1665. https://doi.org/10.1007/s00204-012-0906-3
  16. Mollinedo, F. and Gajate, C. 2003. Microtubules, microtubule- interfering agents and apoptosis. Apoptosis 8, 413-450. https://doi.org/10.1023/A:1025513106330
  17. Schafer, K. A. 1998. The cell cycle: a review. Vet Pathol 35, 461-478. https://doi.org/10.1177/030098589803500601
  18. Shin, D. Y., Kim, G. Y., Lee, J. H., Choi, B. T., Yoo, Y. H. and Choi, Y. H. 2012. Apoptosis induction of human prostate carcinoma DU145 cells by diallyl disulfide via modulation of JNK and PI3K/AKT signaling pathways. Int J Mol Sci 13, 14158-14171. https://doi.org/10.3390/ijms131114158
  19. Terrano, D. T., Upreti, M. and Chambers, T. C. 2010. Cyclin-dependent kinase 1-mediated Bcl-xL/Bcl-2 phosphorylation acts as a functional link coupling mitotic arrest and apoptosis. Mol Cell Biol 30, 640-656. https://doi.org/10.1128/MCB.00882-09
  20. Vermeulen, K., Van Bockstaele, D. R. and Berneman, Z. N. 2003. The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer. Cell Prolif 36, 131-149. https://doi.org/10.1046/j.1365-2184.2003.00266.x
  21. Wang, H. C., Yang, J. H., Hsieh, S. C. and Sheen, L. Y. 2010. Allyl sulfides inhibit cell growth of skin cancer cells through induction of DNA damage mediated G2/M arrest and apoptosis. J Agric Food Chem 58, 7096-7103. https://doi.org/10.1021/jf100613x
  22. Wang, J. and Yi, J. 2008. Cancer cell killing via ROS: to increase or decrease, that is the question. Cancer Biol Ther 7, 1875-1884. https://doi.org/10.4161/cbt.7.12.7067
  23. Wang, J., Yu, Y., Hashimoto, F., Sakata, Y., Fujii, M. and Hou, D. X. 2004. Baicalein induces apoptosis through ROS-mediated mitochondrial dysfunction pathway in HL-60 cells. Int J Mol Med 14, 627-632.
  24. Wong, R. S. 2011. Apoptosis in cancer: from pathogenesis to treatment. J Exp Clin Cancer Res 30, 87. https://doi.org/10.1186/1756-9966-30-87
  25. Wu, C. C., Chung, J. G., Tsai, S. J., Yang, J. H. and Sheen, L. Y. 2004. Differential effects of allyl sulfides from garlic essential oil on cell cycle regulation in human liver tumor cells. Food Chem Toxicol 42, 1937-1947. https://doi.org/10.1016/j.fct.2004.07.008
  26. Wu, X. J., Hu, Y., Lamy, E. and Mersch-Sundermann, V. 2009. Apoptosis induction in human lung adenocarcinoma cells by oil-soluble allyl sulfides: triggers, pathways, and modulators. Environ Mol Mutagen 50, 266-275. https://doi.org/10.1002/em.20467
  27. Yamada, H. Y. and Gorbsky, G. J. 2006. Spindle checkpoint function and cellular sensitivity to antimitotic drugs. Mol Cancer Ther 5, 2963-2969. https://doi.org/10.1158/1535-7163.MCT-06-0319
  28. Yang, J., Xiao, Y. L., He, X. R., Qiu, G. F. and Hu, X. M. 2010. Aesculetin-induced apoptosis through a ROS-mediated mitochondrial dysfunction pathway in human cervical cancer cells. J Asian Nat Prod Res 12, 185-193. https://doi.org/10.1080/10286020903427336
  29. Yang, J. S., Hour, M. J., Huang, W. W., Lin, K. L., Kuo, S. C. and Chung, J. G. 2010. MJ-29 inhibits tubulin polymerization, induces mitotic arrest, and triggers apoptosis via cyclin- dependent kinase 1-mediated Bcl-2 phosphorylation in human leukemia U937 cells. J Pharmacol Exp Ther 334, 477-488. https://doi.org/10.1124/jpet.109.165415
  30. Yogosawa, S., Yamada, Y., Yasuda, S., Sun, Q., Takizawa, K and Sakai, T. 2012. Dehydrozingerone, a structural analogue of curcumin, induces cell-cycle arrest at the G2/M phase and accumulates intracellular ROS in HT-29 human colon cancer cells. J Nat Prod 75, 2088-2093. https://doi.org/10.1021/np300465f