Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Anti-Proliferative Activity of OD78 Is Mediated through Cell Cycle Progression by Upregulation p27kip1 in Rat Aortic Vascular Smooth Muscle Cells

  • Tudev, Munkhtsetseg (College of Pharmacy, Research Center for Bioresource and Health, Chungbuk National University) ;
  • Lim, Yong (Department of Clinical Laboratory Science, Dong-eui University) ;
  • Park, Eun-Seok (College of Pharmacy, Research Center for Bioresource and Health, Chungbuk National University) ;
  • Kim, Won-Sik (College of Pharmacy, Research Center for Bioresource and Health, Chungbuk National University) ;
  • Lim, Il-Ho (College of Pharmacy, Research Center for Bioresource and Health, Chungbuk National University) ;
  • Kwak, Jae-Hwan (College of Pharmacy, Research Center for Bioresource and Health, Chungbuk National University) ;
  • Jung, Jae-Kyung (College of Pharmacy, Research Center for Bioresource and Health, Chungbuk National University) ;
  • Hong, Jin-Tae (College of Pharmacy, Research Center for Bioresource and Health, Chungbuk National University) ;
  • Yoo, Hwan-Soo (College of Pharmacy, Research Center for Bioresource and Health, Chungbuk National University) ;
  • Lee, Mi-Yea (Department of Social Welfare, World Cyber College) ;
  • Pyo, Myoung-Yun (College of Pharmacy, Sookmyung Women's University) ;
  • Yun, Yeo-Pyo (College of Pharmacy, Research Center for Bioresource and Health, Chungbuk National University)
  • Received : 2010.12.13
  • Accepted : 2011.03.15
  • Published : 2011.04.30
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Abstract

Atherosclerosis and post-angiography restenosis are associated with intimal thickening and concomitant vascular smooth muscle cell (VSMC) proliferation. Obovatol, a major biphenolic component isolated from the Magnolia obovata leaf, is known to have anti-inflammatory and anti-tumor activities. The goal of the present study was to enhance the inhibitory effects of obovatol to improve its potential as a preventive or therapeutic agent in atherosclerosis and restenosis. Platelet-derived growth factor (PDGF)-BB-induced proliferation of rat aortic smooth muscle cells (RASMCs) was examined in the presence or absence of a newly synthesized obovatol derivative, OD78. The observed anti-proliferative effect of OD78 was further investigated by cell counting and [$^3H$]-thymidine incorporation assays. Treatment with 1-4 ${\mu}M$ OD78 dose-dependently inhibited the proliferation and DNA synthesis of 25 ng/ml PDGF-BB-stimulated RASMCs. Accordingly, OD78 blocked PDGF-BB-induced progression from the $G_0/G_1$ to S phase of the cell cycle in synchronized cells. OD78 decreased the expression levels of CDK4, cyclin E, and cyclin D1 proteins, as well as the phosphorylation of retinoblastoma protein and proliferating cell nuclear antigen; however, it did not change the CDK2 expression level. In addition, OD78 inhibited downregulation of the cyclin-dependent kinase inhibitor (CKI) $p27^{kip1}$. However, OD78 did not affect the CKI $p21^{cip1}$ or phosphorylation of early PDGF signaling pathway. These results suggest that OD78 may inhibit PDGF-BB-induced RASMC proliferation by perturbing cell cycle progression, potentially through $p27^{kip1}$ pathway activation. Consequently, OD78 may be developed as a potential anti-proliferative agent for the treatment of atherosclerosis and angioplasty restenosis.

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References

  1. Ahn, H. Y., Hadizadeh, K. R., Seul, C., Yun, Y. P., Vetter, H. and Sachinidis, A. (1999) Epigallocathechin-3 gallate selectively inhibits the PDGF-BB-induced intracellular signaling transduction pathway in vascular smooth muscle cells and inhibits transformation of sis-transfected NIH 3T3 fibroblasts and human glioblastoma cells (A172). Mol. Biol. Cell 10, 1093-1104. https://doi.org/10.1091/mbc.10.4.1093
  2. Akiyama, T., Ohuchi, T., Sumida, S., Matsumoto, K. and Toyoshima, K. (1992) Phosphorylation of the retinoblastoma protein by cdk2. Proc. Natl. Acad. Sci. U S A 89, 7900-7904. https://doi.org/10.1073/pnas.89.17.7900
  3. Ammon, H. P. and Wahl, M. A. (1991) Pharmacology of Curcuma longa. Planta. Med. 57, 1-7. https://doi.org/10.1055/s-2006-960004
  4. Blenis, J. (1993) Signal transduction via the MAP kinases: proceed at your own RSK. Proc. Natl. Acad. Sci. U S A 90, 5889-5892. https://doi.org/10.1073/pnas.90.13.5889
  5. Braun-Dullaeus, R. C., Mann, M. J. and Dzau, V. J. (1998) Cell cycle progression: new therapeutic target for vascular proliferative disease. Circulation 98, 82-89. https://doi.org/10.1161/01.CIR.98.1.82
  6. Brooks, E. E., Gray, N. S., Joly, A., Kerwar, S. S., Lum, R., Mackman, R. L., Norman, T. C., Rosete, J., Rowe, M., Schow, S. R., Schultz, P. G., Wang, X., Wick, M. M. and Shiffman, D. (1997) CVT-313, a specific and potent inhibitor of CDK2 that prevents neointimal proliferation. J. Biol. Chem. 272, 29207-29211. https://doi.org/10.1074/jbc.272.46.29207
  7. Chen, D., Krasinski, K., Sylvester, A., Chen, J., Nisen, P. D. and Andres, V. (1997) Downregulation of cyclin-dependent kinase 2 activity and cyclin A promoter activity in vascular smooth muscle cells by p27(KIP1), an inhibitor of neointima formation in the rat carotid artery. J. Clin. Invest. 99, 2334-2341. https://doi.org/10.1172/JCI119414
  8. Choi, M. S., Lee, S. H., Cho, H. S., Kim, Y., Yun, Y. P., Jung, H. Y., Jung, J. K., Lee, B. C., Pyo, H. B. and Hong, J. T. (2007) Inhibitory effect of obovatol on nitric oxide production and activation of NF-kappaB/MAP kinases in lipopolysaccharide-treated RAW 264.7cells. Eur. J. Pharmacol. 556, 181-189. https://doi.org/10.1016/j.ejphar.2006.10.054
  9. Choi, N. H., Choi, G. J., Min, B. S., Jang, K. S., Choi, Y. H., Kang, M. S., Park, M. S., Choi, J. E., Bae, B. K. and Kim, J. C. (2009) Effects of neolignans from the stem bark of Magnolia obovata on plant pathogenic fungi. J. Appl. Microbiol. 106, 2057-2063. https://doi.org/10.1111/j.1365-2672.2009.04175.x
  10. Claesson-Welsh, L. (1994) Platelet-derived growth factor receptor signals. J. Biol. Chem. 269, 32023-32026.
  11. Connell-Crowley, L., Elledge, S. J. and Harper, J. W. (1998) G1 cyclindependent kinases are sufficient to initiate DNA synthesis in quiescent human fibroblasts. Curr. Biol. 8, 65-68. https://doi.org/10.1016/S0960-9822(98)70021-1
  12. Coqueret, O. (2003) New targets for viral cyclins. Cell Cycle 2, 293-295.
  13. Fang, F. and Newport, J. W. (1991) Evidence that the G1-S and G2-M transitions are controlled by different cdc2 proteins in higher eukaryotes. Cell 66, 731-742. https://doi.org/10.1016/0092-8674(91)90117-H
  14. Heldin, C. H., Ostman, A. and Ronnstrand, L. (1998) Signal transduction via platelet-derived growth factor receptors. Biochim. Biophys. Acta. 1378, F79-113.
  15. Hwang, E. I., Kwon, B. M., Lee, S. H., Kim, N. R., Kang, T. H., Kim, Y. T., Park, B. K. and Kim, S. U. (2002) Obovatols, new chitin synthase 2 inhibitors of Saccharomyces cerevisiae from Magnolia obovata. J. Antimicrob. Chemother. 49, 95-101. https://doi.org/10.1093/jac/49.1.95
  16. Ito, K., Iida, T., Ichino, K., Tsunezuka, M., Hattori, M. and Namba, T. (1982) Obovatol and obovatal, novel biphenyl ether lignans from the leaves of Magnolia obovata Thunb. Chem. Pharm. Bull. (Tokyo) 30, 3347-3353. https://doi.org/10.1248/cpb.30.3347
  17. Jirawatnotai, S., Aziyu, A., Osmundson, E. C., Moons, D. S., Zou, X., Kineman, R. D. and Kiyokawa, H. (2004) Cdk4 is indispensable for postnatal proliferation of the anterior pituitary. J. Biol. Chem. 279, 51100-51106. https://doi.org/10.1074/jbc.M409080200
  18. Kim, J. H., Jin, Y. R., Park, B. S., Kim, T. J., Kim, S. Y., Lim, Y., Hong, J. T., Yoo, H. S. and Yun, Y. P. (2005) Luteolin prevents PDGF-BB-induced proliferation of vascular smooth muscle cells by inhibition of PDGF beta-receptor phosphorylation. Biochem. Pharmacol. 69, 1715-1721. https://doi.org/10.1016/j.bcp.2005.04.002
  19. Lee, S. K., Kim, H. N., Kang, Y. R., Lee, C. W., Kim, H. M., Han, D. C., Shin, J., Bae, K. and Kwon, B. M. (2008a) Obovatol inhibits colorectal cancer growth by inhibiting tumor cell proliferation and inducing apoptosis. Bioorg. Med. Chem. 16, 8397-8402. https://doi.org/10.1016/j.bmc.2008.08.033
  20. Lee, S. Y., Yuk, D. Y., Song, H. S., Yoon do, Y., Jung, J. K., Moon, D. C., Lee, B. S. and Hong, J. T. (2008b) Growth inhibitory effects of obovatol through induction of apoptotic cell death in prostate and colon cancer by blocking of NF-kappaB. Eur. J. Pharmacol. 582, 17-25. https://doi.org/10.1016/j.ejphar.2007.12.027
  21. Lee, Y. K., Choi, I. S., Kim, Y. H., Kim, K. H., Nam, S. Y., Yun, Y. W., Lee, M. S., Oh, K. W. and Hong, J. T. (2009) Neurite Outgrowth Effect of 4-O-methylhonokiol by Induction of Neurotrophic Factors Through ERK Activation. Neurochem Res. 34, 2251-2260. https://doi.org/10.1007/s11064-009-0024-7
  22. Lim, Y., Kim, T. J., Jin, Y. R., Kim, D. W., Kwon, J. S., Son, J. H., Jung, J. C., Avery, M. A., Son, D. J., Hong, J. T. and Yun, Y. P. (2007) Epothilone B inhibits neointimal formation after rat carotid injury through the regulation of cell cycle-related proteins. J. Pharmacol. Exp. Ther. 321, 648-655. https://doi.org/10.1124/jpet.106.117622
  23. Lim, Y., Kwon, J. S., Kim, D. W., Lee, S. H., Park, R. K., Lee, J. J., Hong, J. T., Yoo, H. S., Kwon, B. M. and Yun, Y. P. (2010) Obovatol from Magnolia obovata inhibits vascular smooth muscle cell proliferation and intimal hyperplasia by inducing p21Cip1. Atherosclerosis 210, 372-380. https://doi.org/10.1016/j.atherosclerosis.2009.11.037
  24. Majesky, M. W., Reidy, M. A., Bowen-Pope, D. F., Hart, C. E., Wilcox, J. N. and Schwartz, S. M. (1990) PDGF ligand and receptor gene expression during repair of arterial injury. J. Cell Biol. 111, 2149-2158. https://doi.org/10.1083/jcb.111.5.2149
  25. Marra, D. E., Simoncini, T. and Liao, J. K. (2000) Inhibition of vascular smooth muscle cell proliferation by sodium salicylate mediated by upregulation of p21(Waf1) and p27(Kip1). Circulation 102, 2124-2130. https://doi.org/10.1161/01.CIR.102.17.2124
  26. Martin, A., Odajima, J., Hunt, S. L., Dubus, P., Ortega, S., Malumbres, M. and Barbacid, M. (2005) Cdk2 is dispensable for cell cycle inhibition and tumor suppression mediated by p27(Kip1) and p21(Cip1). Cancer Cell 7, 591-598. https://doi.org/10.1016/j.ccr.2005.05.006
  27. Miyauchi, K., Aikawa, M., Tani, T., Nakahara, K., Kawai, S., Nagai, R., Okada, R. and Yamaguchi, H. (1998) Effect of probucol on smooth muscle cell proliferation and dedifferentiation after vascular injury in rabbits: possible role of PDGF. Cardiovasc. Drugs Ther. 12, 251-260. https://doi.org/10.1023/A:1007761631674
  28. Ortega, S., Malumbres, M. and Barbacid, M. (2002) Cyclin D-dependent kinases, INK4 inhibitors and cancer. Biochim. Biophys. Acta. 1602, 73-87.
  29. Pyo, M. K., Lee, Y. and Yun-Choi, H. S. (2002) Anti-platelet effect of the constituents isolated from the barks and fruits of Magnolia obovata. Arch. Pharm. Res. 25, 325-328. https://doi.org/10.1007/BF02976634
  30. Ross, R. (1993) The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 362, 801-809. https://doi.org/10.1038/362801a0
  31. Ross, R. (1995) Cell biology of atherosclerosis. Annu. Rev. Physiol. 57, 791-804. https://doi.org/10.1146/annurev.ph.57.030195.004043
  32. Sasaguri, T., Ishida, A., Kosaka, C., Nojima, H. and Ogata, J. (1996) Phorbol ester inhibits the phosphorylation of the retinoblastoma protein without suppressing cyclin D-associated kinase in vascular smooth muscle cells. J. Biol. Chem. 271, 8345-8351. https://doi.org/10.1074/jbc.271.14.8345
  33. Servant, M. J., Coulombe, P., Turgeon, B. and Meloche, S. (2000) Differential regulation of p27(Kip1) expression by mitogenic and hypertrophic factors: Involvement of transcriptional and posttranscriptional mechanisms. J. Cell. Biol. 148, 543-556. https://doi.org/10.1083/jcb.148.3.543
  34. Sherr, C. J. (1996) Cancer cell cycles. Science 274, 1672-1677. https://doi.org/10.1126/science.274.5293.1672
  35. Sherr, C. J. and Roberts, J. M. (1999) CDK inhibitors: positive and negative regulators of G1-phase progression. Genes. Dev. 13, 1501-1512. https://doi.org/10.1101/gad.13.12.1501
  36. Sriram, V. and Patterson, C. (2001) Cell cycle in vasculoproliferative diseases: potential interventions and routes of delivery. Circulation 103, 2414-2419. https://doi.org/10.1161/01.CIR.103.19.2414
  37. Stroobant, P. and Waterfield, M. D. (1984) Purification and properties of porcine platelet-derived growth factor. EMBO J. 3, 2963-2967.
  38. Tanner, F. C., Boehm, M., Akyurek, L. M., San, H., Yang, Z. Y., Tashiro, J., Nabel, G. J. and Nabel, E. G. (2000) Differential effects of the cyclin-dependent kinase inhibitors p27(Kip1), p21(Cip1), and p16(Ink4) on vascular smooth muscle cell proliferation. Circulation 101, 2022-2025. https://doi.org/10.1161/01.CIR.101.17.2022
  39. Weinberg, R. A. (1995) The retinoblastoma protein and cell cycle control. Cell 81, 323-330. https://doi.org/10.1016/0092-8674(95)90385-2
  40. Yu, J. Y., Lee, J. J., Jung, J. K., Kim, T. J., Yoo, H. S., Yun, Y. P. and Lee, J. C. (2009). JY0691, a newly synthesized obovatol derivative, inhibits cell cycle progression of rat aortic smooth muscle cells through up-regulation of p21(cip1). Eur. J. Pharmacol. 624, 23-30. https://doi.org/10.1016/j.ejphar.2009.09.061