Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
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Inhibition of Cancer Cell Migration by Compounds from Garlic Extracts

마늘추출물에 의한 암세포의 이동 저하

  • Kim, Eun-Kyoung (MRC for Ischemic Tissue Regeneration, Medical Research Institute, Department of Pharmacology, Pusan National University School of Medicine) ;
  • Yun, Sung-Ji (MRC for Ischemic Tissue Regeneration, Medical Research Institute, Department of Pharmacology, Pusan National University School of Medicine) ;
  • Ha, Jung-Min (MRC for Ischemic Tissue Regeneration, Medical Research Institute, Department of Pharmacology, Pusan National University School of Medicine) ;
  • Jin, In-Hye (MRC for Ischemic Tissue Regeneration, Medical Research Institute, Department of Pharmacology, Pusan National University School of Medicine) ;
  • Kim, Young-Whan (MRC for Ischemic Tissue Regeneration, Medical Research Institute, Department of Pharmacology, Pusan National University School of Medicine) ;
  • Kim, Sun-Gun (Department of Natural Resources and Life Sciences, Pusan National University) ;
  • Park, Da-Jung (Department of Natural Resources and Life Sciences, Pusan National University) ;
  • Choi, Young-Whan (Department of Natural Resources and Life Sciences, Pusan National University) ;
  • Yun, Sik (Department of Anatomy, Pusan National School of Medicine) ;
  • Kim, Chi-Dae (MRC for Ischemic Tissue Regeneration, Medical Research Institute, Department of Pharmacology, Pusan National University School of Medicine) ;
  • Bae, Sun-Sik (MRC for Ischemic Tissue Regeneration, Medical Research Institute, Department of Pharmacology, Pusan National University School of Medicine)
  • 김은경 (허혈조직재생연구센터, 부산대학교 의학전문대학원 약리학교실) ;
  • 윤성지 (허혈조직재생연구센터, 부산대학교 의학전문대학원 약리학교실) ;
  • 하정민 (허혈조직재생연구센터, 부산대학교 의학전문대학원 약리학교실) ;
  • 진인혜 (허혈조직재생연구센터, 부산대학교 의학전문대학원 약리학교실) ;
  • 김영환 (허혈조직재생연구센터, 부산대학교 의학전문대학원 약리학교실) ;
  • 김선근 (부산대학교 생명자원과학대학) ;
  • 박다정 (부산대학교 생명자원과학대학) ;
  • 최영환 (부산대학교 생명자원과학대학) ;
  • 윤식 (부산대학교 의학전문대학원 해부학교실) ;
  • 김치대 (허혈조직재생연구센터, 부산대학교 의학전문대학원 약리학교실) ;
  • 배순식 (허혈조직재생연구센터, 부산대학교 의학전문대학원 약리학교실)
  • Received : 2011.03.22
  • Accepted : 2011.04.13
  • Published : 2011.06.30
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Abstract

Cell migration plays a fundamental role in cancer cell invasion and metastasis as well as in many physiological responses. Here, we screened four different sources of garlic - water extract of normal and black garlic, as well as dried normal and black garlic - for the identification of anti-invasive and anti-metastatic activity on cancer cells. Inhibition of cancer cell migration was observed in the hexane extract of dried-garlic. Inhibitory activity was further purified to near homogeneity by thin layer chromatography and named $\b{i}$nhibitor of $\b{c}$ancer $\b{m}$etastasis from garlic #27 (ICMG-27). ICMG-27 completely blocked insulin-like growth factor-1 (IGF-1)-induced OVCAR-3 cell migration at 6 ${\mu}g/ml$. ICMG-27 completely blocked IGF-1-induced OVCAR-3 and NIH-3T3 cell migration whereas IGF-1-induced mouse embryonic fibroblast (MEF) cell migration was not affected byICMG-27. ICMG-27 inhibited all the tested IGF-1-induced cancer cell migration such as OVCAR-3, SKOV-3, and MDA-MB-231 cells. Finally, ICMG-27 could inhibit IGF-1-, lysophosphatidic acid (LPA)-, sphingosine-1-phosphate (S1P)-, leukotriene B4 (LTB4)-, and angiotensin II (AngII)-induced OVCAR-3 cell migration. These results indicate that ICMG-27 inhibits cancer cell migration by blocking essential steps in many agonists-induced cancer cell migrations. Unveiling an anti-invasive mechanism of ICMG-27 on cancer cells will provide a basis for cancer therapy.

세포의 이동은 많은 생리적 반응뿐만 아니라 암 세포 침윤과 전이에 중요한 역할을 수행한다. 본 연구에서는 마늘이 암세포의 이동에 미치는 영향을 확인하기 위해, 표준 마늘과 흑마늘을 준비하고 이들을 각각 물을 이용하여 추출하거나 건조하여 추출한 추출물 4 종류를 이용하여 항침윤성과 항전이성에 대해 조사하였다. 실험결과, 암세포의 이동은 건조 후 헥산으로 추출한 분획에 암세포의 이동 억제 활성이 관찰되었다. 이 분획을 박막 크로마토그래피를 이용하여 분리정제하였으며, 이를 inhibitor of cancer metastasis from garlic #27 (ICMG-27)이라 명명하였다. ICMG-27 (6 ${\mu}g/ml$)을 세포에 처리하였을 때, IGF-1에 의한 OVCAR-3와 NIH-3T3 세포의 이동을 억제함을 확인하였다. 그러나 ICMG-27은 mouse embryonic fibroblast (MEF) 세포에서 IGF-1에 의한 이동에는 영향을 주지 않았다. 이러한 ICMG-27은 OVCA-3, SKOV-3와 MDA-MB-231 세포와 같은 암세포에서 모두 IGF-1에 의한 이동을 억제함을 관찰하였다. 마지막으로 세포이동을 일으키는 인자에 따른 ICMG-27의 영향을 확인한 것으로, IGF-1, lysophosphatidic acid (LPA), sphingosine-1-phosphate (S1P), leukotriene B4 (LTB4) 그리고, angiotensinII (AngII)에 의한 OVCAR-3 세포의 이동을 모두 억제하였다. 이러한 결과를 바탕으로, ICMG-27은 암세포의 이동을 유도하는 많은 인자들에 의한 필수적인 단계를 차단함으로써, 암세포의 이동을 억제하는 것을 확인 할 수 있었으며, ICMG-27에 의한 암세포의 항 침윤 메커니즘의 규명은 암환자의 치료에 기초적인 발판을 제공할 것입니다.

Keywords

References

  1. Bae, S. S., H. Cho, J. Mu, and M. J. Birnbaum. 2003. Isoform-specific regulation of insulin-dependent glucose uptake by Akt/protein kinase B. J. Biol. Chem. 278, 49530-49536. https://doi.org/10.1074/jbc.M306782200
  2. Chu, Q., D. T. Lee, S. W. Tsao, X. Wang, and Y. C. Wong. 2007. S-allylcysteine, a water-soluble garlic derivative, suppresses the growth of a human androgen-independent prostate cancer xenograft, CWR22R, under in vivo conditions. BJU Int. 99, 925-932. https://doi.org/10.1111/j.1464-410X.2006.06639.x
  3. Chu, Q., M. T. Ling, H. Feng, H. W. Cheung, S. W. Tsao, X. Wang, and Y. C. Wong. 2006. A novel anticancer effect of garlic derivatives: inhibition of cancer cell invasion through restoration of E-cadherin expression. Carcinogenesis 27, 2180-2189. https://doi.org/10.1093/carcin/bgl054
  4. Do, K. H., Y. W. Choi, E. K. Kim, S. J. Yun, M. S. Kim, S. Y. Lee, J. M. Ha, J. H. Kim, C. D. Kim, B. G. Son, J. S. Kang, I. A. Khan, and S. S. Bae. 2009. Pinoresinol-4,4'-di-O-β -D-glucoside from Valeriana officinalis root stimulates calcium mobilization and chemotactic migration of mouse embryo fibroblasts. Phytomedicine 16, 530-537. https://doi.org/10.1016/j.phymed.2008.12.002
  5. Duan, C., J. R. Bauchat, and T. Hsieh. 2000. Phosphatidylinositol 3-kinase is required for insulin-like growth factor-I-induced vascular smooth muscle cell proliferation and migration. Circ. Res. 86, 15-23. https://doi.org/10.1161/01.RES.86.1.15
  6. Dunn, S. E., M. Ehrlich, N. J. Sharp, K. Reiss, G. Solomon, R. Hawkins, R. Baserga, and J. C. Barrett. 1998. A dominant negative mutant of the insulin-like growth factor-I receptor inhibits the adhesion, invasion, and metastasis of breast cancer. Cancer Res. 58, 3353-3361.
  7. Gupta, G. P. and J. Massague. 2006. Cancer metastasis: building a framework. Cell 127, 679-695. https://doi.org/10.1016/j.cell.2006.11.001
  8. Hanahan, D. and R. A. Weinberg. 2000. The hallmarks of cancer. Cell 100, 57-70. https://doi.org/10.1016/S0092-8674(00)81683-9
  9. Herman-Antosiewicz, A. and S. V. Singh. 2004. Signal transduction pathways leading to cell cycle arrest and apoptosis induction in cancer cells by Allium vegetable-derived organosulfur compounds: a review. Mutat. Res. 555, 121-131. https://doi.org/10.1016/j.mrfmmm.2004.04.016
  10. Howard, E. W., M. T. Ling, C. W. Chua, H. W. Cheung, X. Wang, and Y. C. Wong. 2007. Garlic-derived S-allylmercaptocysteine is a novel in vivo antimetastatic agent for androgen- independent prostate cancer. Clin. Cancer Res. 13, 1847-1856. https://doi.org/10.1158/1078-0432.CCR-06-2074
  11. Hsing, A.W., A. P. Chokkalingam, Y. T. Gao, M. P. Madigan, J. Deng, G. Gridley, and J. F. Fraumeni, Jr. 2002. Allium vegetables and risk of prostate cancer: a population-based study. J. Natl. Cancer Inst. 94, 1648-1651. https://doi.org/10.1093/jnci/94.21.1648
  12. Hu, X., B. N. Cao, G. Hu, J. He, D. Q. Yang, and Y. S. Wan, 2002. Attenuation of cell migration and induction of cell death by aged garlic extract in rat sarcoma cells. Int. J. Mol. Med. 9, 641-643.
  13. Irani, C., E. A. Goncharova, D. S. Hunter, C. L. Walker, R. A. Panettieri, and V. P. Krymskaya. 2002. Phosphatidylinositol 3-kinase but not tuberin is required for PDGF-induced cell migration. Am. J. Physiol. Lung Cell Mol. Physiol. 282, L854-L862.
  14. Kim, E. K., D. F. Tucker, S. J. Yun, K. H. Do, M. S. Kim, J. H. Kim, C. D. Kim, M. J. Birnbaum, and S. S. Bae. 2008. Linker region of Akt1/protein kinase Bα mediates platelet- derived growth factor-induced translocation and cell migration. Cell Signal 20, 2030-2037. https://doi.org/10.1016/j.cellsig.2008.07.012
  15. Kim, E. K., S. J. Yun, K. H. Do, M. S. Kim, M. Cho, D. S. Suh, C. D. Kim, J. H. Kim, M. J. Birnbaum, and S. S. Bae. 2008. Lysophosphatidic acid induces cell migration through the selective activation of Akt1. Exp. Mol. Med. 40, 445-452. https://doi.org/10.3858/emm.2008.40.4.445
  16. Larue, L. and A. Bellacosa. 2005. Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3' kinase/AKT pathways. Oncogene 24, 7443-7454. https://doi.org/10.1038/sj.onc.1209091
  17. Metzner, B., M. Barbisch, F. Bachmann, W. Czech, and J. Norgauer. 1996. Evidence of the involvement of phosphatidylinositol 3-kinase in the migration, actin stress fiber formation, and $\alpha$v $\beta$3-integrin-mediated adherence of human melanoma cells. J. Invest. Dermatol. 107, 597-602. https://doi.org/10.1111/1523-1747.ep12583096
  18. Nelson, W. G., A. M. De Marzo, and W. B. Isaacs. 2003. Prostate cancer. N. Engl. J. Med. 349, 366-381. https://doi.org/10.1056/NEJMra021562
  19. Price, J. T., T. Tiganis, A. Agarwal, D. Djakiew, and E. W. Thompson. 1999. Epidermal growth factor promotes MDA-MB-231 breast cancer cell migration through a phosphatidylinositol 3'-kinase and phospholipase C-dependent mechanism. Cancer Res. 59, 5475-5478.
  20. Tai, Y. T., K. Podar, L. Catley, Y. H. Tseng, M. Akiyama, R. Shringarpure, R. Burger, T. Hideshima, D. Chauhan, N. Mitsiades, P. Richardson, N. C. Munshi, C. R. Kahn, C. Mitsiades, and K. C. Anderson. 2003. Insulin-like growth factor-1 induces adhesion and migration in human multiple myeloma cells via activation of beta1-integrin and phosphatidylinositol 3'-kinase/AKT signaling. Cancer Res. 63, 5850-5858.
  21. Thomson, M. and M. Ali. 2003. Garlic [Allium sativum]: a review of its potential use as an anti-cancer agent. Curr. Cancer Drug Targets 3, 67-81. https://doi.org/10.2174/1568009033333736
  22. van Golen, C. M., T. S. Schwab, B. Kim, M. E. Soules, S. Su Oh, K. Fung, K. L. van Golen, and E. L. Feldman. 2006. Insulin-like growth factor-I receptor expression regulates neuroblastoma metastasis to bone. Cancer Res. 66, 6570-6578. https://doi.org/10.1158/0008-5472.CAN-05-1448
  23. Wu, Y., S. Yakar, L. Zhao, L. Hennighausen, and D. LeRoith. 2002. Circulating insulin-like growth factor-I levels regulate colon cancer growth and metastasis. Cancer Res. 62, 1030-1035.
  24. Xiao, D., J. T. Pinto, J. W. Soh, A. Deguchi, G. G. Gundersen, A. F. Palazzo, J. T. Yoon, H. Shirin, and I. B. Weinstein. 2003. Induction of apoptosis by the garlic-derived compound S-allylmercaptocysteine (SAMC) is associated with microtubule depolymerization and c-Jun NH(2)-terminal kinase 1 activation. Cancer Res. 63, 6825-6837.
  25. Xiao, D., S. Choi, D. E. Johnson, V. G. Vogel, C. S. Johnson, D. L. Trump, Y. J. Lee, and S. V. Singh. 2004. Diallyl trisulfide- induced apoptosis in human prostate cancer cells involves c-Jun N-terminal kinase and extracellular-signal regulated kinase-mediated phosphorylation of Bcl-2. Oncogene 23, 5594-5606. https://doi.org/10.1038/sj.onc.1207747
  26. You, W. C., W. J. Blot, Y. S. Chang, A. Ershow, Z. T. Yang, Q. An, B. E. Henderson, J. F. Fraumeni, and T. G. Wang. 1989. Allium vegetables and reduced risk of stomach cancer. J. Natl. Cancer Inst. 81, 162-164. https://doi.org/10.1093/jnci/81.2.162

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