Effect of Lindera obtusiloba extract on cancer metastasis

생강나무 추출물의 암전이 억제효과

  • Yun, Hyuk (Dept. of Internal Medicine, College of Oriental Medicine, Won-Kwang University) ;
  • Lee, Yong-Jae (College of Pharmacy, Woo-Suk University) ;
  • Seo, Hyun-Won (College of Pharmacy, Woo-Suk University) ;
  • Park, Kyoung-Jae (College of Pharmacy, Woo-Suk University) ;
  • Ko, Ha-Neul (Dept. of Internal Medicine, College of Oriental Medicine, Won-Kwang University) ;
  • Cha, Dong-Seok (College of Pharmacy, Woo-Suk University) ;
  • Kwon, Jin (Dept. of Prosthetics and Orthotics, Korea National College of Rehabilitation and Welfare) ;
  • Jeon, Hoon (College of Pharmacy, Woo-Suk University) ;
  • Kim, Kang-San (Dept. of Internal Medicine, College of Oriental Medicine, Won-Kwang University)
  • 윤혁 (원광대학교 한의과대학 내과학교실) ;
  • 이용재 (우석대학교 약학대학) ;
  • 서현원 (우석대학교 약학대학) ;
  • 박경재 (우석대학교 약학대학) ;
  • 고하늘 (원광대학교 한의과대학 내과학교실) ;
  • 차동석 (우석대학교 약학대학) ;
  • 권진 (한국재활복지대학 의료보장구과) ;
  • 전훈 (우석대학교 약학대학) ;
  • 김강산 (원광대학교 한의과대학 내과학교실)
  • Published : 2012.12.30

Abstract

Objectives : In the present study, anti-metastatic properties of the methanol extract of L. obtusiloba (MLO) were evaluated. Methods : To determine the effect of MLO on cancer metastasis, we checked matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) activities and expressions in B16F10 melanoma cells. In addition, we performed cell migration assay as well as invasion assay using Matrigel. Finally, we used an in vivo lung metastasis model to confirm the anti-metastatic activity of MLO. Results : 1. MLO showed potent inhibitory effects on MMP-2 and MMP-9 activities and expressions via down-regulation of activation of NF-${\kappa}B$ in B16F10 melanoma cells. 2. Melanoma cell migration and invasion were down-regulated by MLO treatment. 3. Not only in vitro model, but MLO also significantly suppressed lung metastasis in vivo. Conclusions : The present results indicate that MLO has strong inhibitory effect on cancer metastasis. Therefore, L. obtusiloba could be a valuable anti-metastatic agent.

목 적 : 본 연구에서는 생강나무 메탄올 추출물이 암전이 억제에 미치는 영향을 조사하고자 하였다. 방 법 : 생강나무 추출물의 암전이 억제능을 확인하기 위해서 B16F10 흑색종 세포를 이용하여 금속단백분해효소의 활성 및 발현을 측정하였으며, 암세포의 이동능이나 침윤능도 조사하였다. 폐전이 동물모델에서 생강나무 추출물이 미치는 영향을 조사하여 활성을 최종적으로 확인하였다. 결 과 : 1. 생강나무 추출물은 B16F10 흑색종 세포에서 뚜렷한 금속단백분해효소의 효소활성 및 발현 억제효과를 보였으며 이는 NF-${\kappa}B$의 활성 억제에서 기인한 것임을 확인하였다. 2. 흑색종 세포의 이동이나 침윤 역시 생강나무 추출물 투여에 의해 현저히 감소하였다. 3. 폐전이 동물 모델에서도 생강나무 추출물에 의해 폐로 전이되 집락의 수가 감소하였다. 결 론 : 이상의 결과로 생강나무 추출물은 뛰어난 암전이 억제효과가 있는 것을 확인할 수 있었으며, 전이성 암치료에 있어서 유용하게 사용될 수 있을 것으로 사료된다.

Keywords

Acknowledgement

Supported by : Won-kwang university

References

  1. Arvelo F, Cotte, C. Metalloproteinases in tumor progression. Review Invest Clin 2006;47(2) :185-205.
  2. Baek WK, Park JW, Lim JH, Suh SI, Suh MH, Gabrielson E, et al. Molecular cloning and characterization of the human budding uninhibited by benomyl (BUB3) promoter. Gene 2002;295(1):117-23. https://doi.org/10.1016/S0378-1119(02)00827-2
  3. Gao Z, Sasaoka T, Fujimori T, Oya T, Ishii Y, Sabit H, et al. Deletion of the PDGFR-beta gene affects key fibroblast functions important for wound healing. J Biol Chem 2005;280(10) :9375-89. https://doi.org/10.1074/jbc.M413081200
  4. Hrabec E, Strek M, Nowak D, Greger J, Suwalski M, Hrabec Z. Activity of type IV collagenases (MMP-2 and MMP-9) in primary pulmonary carcinomas: a quantitative analysis. J Cancer Res Clin Oncol 2002;128(4):197-204. https://doi.org/10.1007/s00432-001-0320-3
  5. Jiang J, Grieb B, Thyagarajan A, Sliva D. Ganoderic acids suppress growth and invasive behavior of breast cancer cells by modulating AP-1 and NF-${\kappa}B$ signaling. Int J Mol Med 2008;21(5):577-84.
  6. Johnsen M, Lund LR, Romer J, Almholt K, Dano K. Cancer invasion and tissue remodeling: common themes in proteolytic matrix degradation. Curr Opin Cell Biol 1998;10(5):667-71. https://doi.org/10.1016/S0955-0674(98)80044-6
  7. Kohn EC, Liotta LA. Molecular insights into cancer invasion: strategies for prevention and intervention. Cancer Res 1995;55(9):1856-62.
  8. Komae H, Hayashi H. Phytosterols of the trunks of Lindera obtusiloba. Phytochemistry 1972;11:1182. https://doi.org/10.1016/S0031-9422(00)88485-X
  9. Kim MM, Ta QV, Mendis E, Rajapakse N, Jung WK, Byun HG, et al. Phlorotannins in Ecklonia cava extract inhibit matrix metalloproteinase activity. Life Sci 2006;79(15):1436-43. https://doi.org/10.1016/j.lfs.2006.04.022
  10. Kim SH, Son JH, Lee SH. Inhibitory effects of water extract of Lindera obtusiloba on the mast cell-mediated allergic inflammation. Kor J Pharmacogn 2009;40(3):233-7.
  11. Kwon HC, Baek NI, Choi SU, Lee KR. New cytotoxic butanolides from Lindera obtusiloba BLUME. Chem Pharm Bull 2000;48(5):614-6. https://doi.org/10.1248/cpb.48.614
  12. Kwon HC, Choi SU, Lee JO, Bae KH, Zee OP, Lee KR. Two new lignans from Lindera obtusiloba blume. Arch Pharm Res 1999;22(4) :417-22. https://doi.org/10.1007/BF02979069
  13. Lee KY, Kim SH, Jeong EJ, Park JH, Kim SH, Kim YC, et al. New secoisolariciresinol derivatives from Lindera obtusiloba stems and their neuroprotective activities. Planta Med 2010;76(3):294-7. https://doi.org/10.1055/s-0029-1186053
  14. Liabakk NB, Talbot I, Smith RA, Wilkinson K, Balkwill F. Matrix metalloprotease 2 (MMP-2) and matrix metalloprotease 9 (MMP-9) type IV collagenases in colorectal cancer. Cancer Res 1996;56(15):190-6.
  15. Lind DS, Hochwald SN, Malaty J, Rekkas S, Heby P, Mishra G. Nuclear factor-${\kappa}B$ is unregulated in colorectal cancer. Surgery 2001; 130(2):363-9. https://doi.org/10.1067/msy.2001.116672
  16. McCawley LJ, Matrisian LM. Matrix metalloproteinases: multifunctional contributors to tumor progression. Mol Med Today 2000;6(4):149-56. https://doi.org/10.1016/S1357-4310(00)01686-5
  17. Nakshatri H, Bhat-Nakshatri P, Martin DA, Goulet RJ, Sledge GW. Constitutive activation of NF-${\kappa}B$ during progression of breast cancer to hormone independent growth. Mol Cell Biol 1997;17(7):3629-39. https://doi.org/10.1128/MCB.17.7.3629
  18. Niwa M, Iguchi M, Yamamura S. Three new obtusilactones from Lindera obtusiloba Blume. Chemistry Letters 1975;4:655-8. https://doi.org/10.1246/cl.1975.655
  19. Oppenheimer SB. Cellular basis of cancer metastasis: A review of fundamentals and neadvances. Acta Histochem 2006;108(5):327-34. https://doi.org/10.1016/j.acthis.2006.03.008
  20. Zhao W, Liu H, Xu S, Entschladen F, Niggemann B, Zänker KS, et al. Migration and metalloproteinases determine the invasive potential of mouse melanoma cells, but not melanin and telomerase. Cancer Lett 2001;162:S49-S55. https://doi.org/10.1016/S0304-3835(00)00656-X
  21. Ruehl M, Erben U, Kim K, Freise C, Dagdelen T, Eisele S, et al. Extracts of Lindera obtusiloba induce antifibrotic effects in hepatic stellate cells via suppression of a TGF-beta -mediated profibrotic gene expression pattern. J Nutr Biochem 2009;20(8):597-606. https://doi.org/10.1016/j.jnutbio.2008.06.003
  22. Scorilas A, Karameris A, Arnogiannaki N, Ardavanis A, Bassilopoulos P, Trangas T, et al. Overexpression of matrix-metalloproteinase-9 in human breast cancer: a potential favourable indicator in node-negative patients. Br J Cancer 2001;84(11):1488-96. https://doi.org/10.1054/bjoc.2001.1810
  23. Shishodia S, Majumdar S, Banerjee S, Aggarwal BB. Ursolic acid inhibits nuclear factor-kappaB activation induced by carcinogenic agents through suppression of IkappaBalpha kinase and p65 phosphorylation: correlation with down-regulation of cyclooxygenase 2, matrix metalloproteinase 9, and cyclin D1. Cancer Res 2003;63(15):4375-83.
  24. Tryggvason K, Hoyhtya M, Salo T. Proteolytic degradation of extracellularmatrix in tumor invasion. Biochimica et Biophysica Acta 1987; 907(3):191-217.
  25. Yang J, Richmond A. Constitutive IkappaB kinase activity correlates with nuclear factorkappaB activation in human melanoma cells. Cancer Res 2001;61(12):4901-9.
  26. Yeh CT, Wu CH, Yen GC. Ursolic acid, a naturally occurring triterpenoid, suppresses migration and invasion of human breast cancer cells by modulating c-Jun N-terminal kinase, Akt and mammalian target of rapamycin signaling. Mol Nutr Food Res 2010;54(9):1285-95. https://doi.org/10.1002/mnfr.200900414
  27. Yook C. Lindera obtusiloba. Medical plants of Korea. Seoul: Jinmyeong Publishing Co.; 1989, p. 184.
  28. Yoon SO, Park SJ, Yun CH, Chung AS. Roles of matrix metalloproteinases in tumor metastasis and angiogenesis. J Biochem Mol Biol 2003; 36(1):128-37. https://doi.org/10.5483/BMBRep.2003.36.1.128