Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지
DOI QR코드

DOI QR Code

Inhibitory Effects of Phylligenin on the Proliferation of Cultured Rat Neural Progenitor Cells

  • Lee, Sung-Hoon (Department of Pharmacology, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University) ;
  • Go, Hyo-Sang (Department of Pharmacology, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University) ;
  • Choi, Chang-Soon (Department of Pharmacology, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University) ;
  • Cheong, Jae-Hoon (Department of Pharmacy, Sahmyook University) ;
  • Han, Sun-Young (Pharmacology Research Center, Korea Research Institute of Chemical Technology) ;
  • Bae, Ki-Hwan (College of Pharmacy, Chungnam University) ;
  • Ko, Kwang-Ho (Department of Pharmacology, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University) ;
  • Park, Seung-Hwa (Center for Geriatric Neuroscience Research, IBST, and Research Institute of Medical Sciences, School of Medicine, Konkuk University)
  • Published : 2010.01.31
Download PDF
⟨ Previous Next ⟩

Abstract

Neural progenitor cells (NPCs) differentiate into astrocytes, neurons and oligodendrocytes, which is controlled by various factors in brain. Recent evidences suggest that small molecules modulating the proliferation and differentiation of NPCs may have therapeutic value as well as the potential use as chemical probes. Phylligenin is a lignan with anti-inflammatory activity that is isolated from the fruits of Forsythia koreana. We investigated effects of phylligenin on proliferation and differentiation of NPCs. Treatment of phylligenin decreased the number of proliferating NPCs in culture without effects on the differentiation and survival of neural cells such as neurons and astrocytes. To examine the mechanism of the decreased NPCs number, we performed cell cycle analysis. Proliferation of NPCs was decreased via G1-S transition block by phylligenin treatment, and it was mediated by the increase of p21 level. However, phylligenin did not induce apoptosis of NPCs as determined by TUNEL assay and PARP cleavage. We also found that viability of glioma cell lines such as C6 and U87MG glioma cells, but not that of primary neuron and astrocyte, was inhibited by phylligenin. These results suggest that phylligenin selectively inhibits proliferation of rapidly growing cells such as neural stem cells and glioma cells. Given that the possible role of brain tumor stem cells in the pathology of brain cancers, the inhibitory effects of phylligenin might be useful in the development of new therapeutic agents against brain cancers.

Keywords

References

  1. Benoit, B. O., Savarese, T., Joly, M., Engstrom, C. M., Pang, L., Reilly, J., Recht, L. D., Ross, A. H. and Quesenberry, P. J. (2001). Neurotrophin channeling of neural progenitor cell differentiation. J. Neurobiol. 46, 265-280. https://doi.org/10.1002/1097-4695(200103)46:4<265::AID-NEU1007>3.0.CO;2-B
  2. Cavin, A., Potterat, O., Wolfender, J. L., Hostettmann, K. and Dyatmyko, W. (1998). Use of on-flow LC/1H NMR for the study of an antioxidant fraction from Orophea enneandra and isolation of a polyacetylene, lignans, and a tocopherol derivative. J. Nat. Prod. 61, 1497-1501. https://doi.org/10.1021/np980203p
  3. Conover, J. C. and Notti, R. Q. (2008). The neural stem cell niche. Cell Tissue Res. 331, 211-224. https://doi.org/10.1007/s00441-007-0503-6
  4. Conti, L., Pollard, S. M., Gorba, T., Reitano, E., Toselli, M., Biella, G., Sun, Y., Sanzone, S., Ying, Q. L., Cattaneo, E. and Smith, A. (2005). Niche-independent symmetrical selfrenewal of a mammalian tissue stem cell. PLoS. Biol. 3, e283. https://doi.org/10.1371/journal.pbio.0030283
  5. Diamandis, P., Sacher, A. G., Tyers, M. and Dirks, P. B. (2009). New drugs for brain tumors? Insights from chemical probing of neural stem cells. Med. Hypotheses 72, 683-687. https://doi.org/10.1016/j.mehy.2008.10.034
  6. Diamandis, P., Wildenhain, J., Clarke, I. D., Sacher, A. G., Graham, J., Bellows, D. S., Ling, E. K., Ward, R. J., Jamieson, L. G., Tyers, M. and Dirks, P. B. (2007). Chemical genetics reveals a complex functional ground state of neural stem cells. Nat. Chem. Biol. 3, 268-273. https://doi.org/10.1038/nchembio873
  7. Gage, F. H. (2000). Mammalian neural stem cells. Science 287, 1433-1438. https://doi.org/10.1126/science.287.5457.1433
  8. Kim, S. J., Son, T. G., Park, H. R., Park, M., Kim, M. S., Kim, H. S., Chung, H. Y., Mattson, M. P. and Lee, J. (2008). Curcumin stimulates proliferation of embryonic neural progenitor cells and neurogenesis in the adult hippocampus. J. Biol. Chem. 283, 14497-14505. https://doi.org/10.1074/jbc.M708373200
  9. Lim, H., Lee, J. G., Lee, S. H., Kim, Y. S. and Kim, H. P. (2008). Anti-inflammatory activity of phylligenin, a lignan from the fruits of Forsythia koreana, and its cellular mechanism of action. J. Ethnopharmacol. 118, 113-117. https://doi.org/10.1016/j.jep.2008.03.016
  10. Martino, G., and Pluchino, S. (2006). The therapeutic potential of neural stem cells. Nat. Rev. Neurosci. 7, 395-406.
  11. Piccirillo, S. G., Reynolds, B. A., Zanetti, N., Lamorte, G., Binda, E., Broggi, G., Brem, H., Olivi, A., Dimeco, F. and Vescovi, A. L. (2006). Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature 444, 761-765.
  12. Qiang, L., Yang, Y., Ma, Y. J., Chen, F. H., Zhang, L. B., Liu, W., Qi, Q., Lu, N., Tao, L., Wang, X. T., You, Q. D. and Guo, Q. L. (2009). Isolation and characterization of cancer stem like cells in human glioblastoma cell lines. Cancer Lett. 279, 13-21. https://doi.org/10.1016/j.canlet.2009.01.016
  13. Rishton, G. M. (2008). Small molecules that promote neurogenesis in vitro. Recent Pat. CNS Drug Discov. 3, 200-208. https://doi.org/10.2174/157488908786242425
  14. Saxe, J. P., Wu, H., Kelly, T. K., Phelps, M. E., Sun, Y. E., Kornblum, H. I. and Huang, J. (2007). A phenotypic smallmolecule screen identifies an orphan ligand-receptor pair that regulates neural stem cell differentiation. Chem. Biol. 14, 1019-1030. https://doi.org/10.1016/j.chembiol.2007.07.016
  15. Schneider, J. W., Gao, Z., Li, S., Farooqi, M., Tang, T. S., Bezprozvanny, I., Frantz, D. E. and Hsieh, J. (2008). Smallmolecule activation of neuronal cell fate. Nat. Chem. Biol. 4, 408-410. https://doi.org/10.1038/nchembio.95
  16. 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
  17. Shin, C. Y., Choi, J. W., Jang, E. S., Ju, C., Kim, W. K., Kim, H. C., Choi, C. R., and Ko, K. H. (2001). Dehydroepiandrosterone inhibits the death of immunostimulated rat C6 glioma cells deprived of glucose. Brain Res. 922, 267-275. https://doi.org/10.1016/S0006-8993(01)03185-7
  18. Shin, C. Y., Choi, J. W., Ryu, J. R., Ko, K. H., Choi, J. J., Kim, H. S., Lee, J. C., Lee, S. J., Kim, H. C. and Kim, W. K. (2002). Glucose deprivation decreases nitric oxide production via NADPH depletion in immunostimulated rat primary astrocytes. Glia 37, 268-274. https://doi.org/10.1002/glia.10032
  19. Singh, S. K., Clarke, I. D., Hide, T. and Dirks, P. B. (2004). Cancer stem cells in nervous system tumors. Oncogene. 23, 7267-7273. https://doi.org/10.1038/sj.onc.1207946
  20. Singh, S. K., Clarke, I. D., Terasaki, M., Bonn, V. E., Hawkins, C., Squire, J. and Dirks, P. B. (2003). Identification of a cancer stem cell in human brain tumors. Cancer Res. 63, 5821-5828.
  21. Stiles, C. D. and Rowitch, D. H. (2008). Glioma stem cells: a midterm exam. Neuron 58, 832-846. https://doi.org/10.1016/j.neuron.2008.05.031
  22. Temple, S. (2001). The development of neural stem cells. Nature 414, 112-117. https://doi.org/10.1038/35102174
  23. Vescovi, A. L., Galli, R. and Reynolds. B. A. (2006). Brain tumour stem cells. Nat. Rev. Cancer 6, 425-436. https://doi.org/10.1038/nrc1889
  24. Warashina, M., Min, K. H., Kuwabara, T., Huynh, A., Gage, F. H., Schultz, P. G. and Ding, S. (2006). A synthetic small molecule that induces neuronal differentiation of adult hippocampal neural progenitor cells. Angew. Chem. Int. Ed. Engl. 45, 591-593. https://doi.org/10.1002/anie.200503089
  25. Weinberg, W. C. and Denning, M. F. (2002). P21Waf1 control of epithelial cell cycle and cell fate. Crit. Rev. Oral Biol. Med. 13, 453-464. https://doi.org/10.1177/154411130201300603
  26. Zhou, X. D., Wang, X. Y., Qu, F. J., Zhong, Y. H., Lu, X. D., Zhao, P., Wang, D. H., Huang, Q. B., Zhang, L. and Li, X. G. (2009). Detection of cancer stem cells from the C6 glioma cell line. J. Int. Med. Res. 37, 503-510. https://doi.org/10.1177/147323000903700226