Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지

Effects of Tubulyzines, Novel Microtubule-Binding Triazine Molecules, on Endothelial Progenitor Cell Differentiation

  • Park, Hyo-Eun (Cancer Research Institute, Catholic Research Institutes of Medical Sciences, The Catholic University of Korea) ;
  • Lee, Soo-Young (Department of Natural Sciences, College of Medicine, The Catholic University of Korea) ;
  • Ahn, Hyun-Young (Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, The Catholic University of Korea) ;
  • Shin, Jong-Cheol (Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, The Catholic University of Korea) ;
  • Chang, Young-Tae (Department of Chemistry, New York University) ;
  • Joe, Young-Ae (Cancer Research Institute, Catholic Research Institutes of Medical Sciences, The Catholic University of Korea)
  • Published : 2003.06.01
Download PDF
⟨ Previous Next ⟩

Abstract

Microtubule-binding molecules have been developed as anti-cancer agents to overcome the toxicities of current chemotherapeutics and also have potential for use as anti-angiogenic agents. In this work, we examined the effect of novel triazine compounds, Tubulyzines (microTUBUle LYsing triaZINE), derived from the orthogonal synthesis of a triazine library, on endothelial progenitor cell differentiation. When mononuclear cells isolated from human cord blood were cultured on fibronectin-coated plates for 7 days, all the Tubulyzine compounds A, B, and C (TA, TB, and TC) tested decreased the number of adherent cells in a dose-dependent manner in a coo. centration ranges of 2-5 to $80\mu\textrm{M}$. TA ($IC_{50}$=$20\mu\textrm{M}$) showed slightly more potent activity than TB and TC. Adherent cells treated with TA also exhibited a lower level of ability to ac-LDL uptake, with low ratios of positive cells out of total adherent cells, in a dose-dependent manner and weak expression of endothelial lineage markers, KDR, CD31, and vWF at $20\mu\textrm{M}$. Therefore, these results suggest that tubulyzine A (TA) can be effectively used for the inhibition of new vessel growth by inhibiting differentiation of endothelial progenitor cells.

Keywords

References

  1. Asahara T., Murohara T., Sullivan M., van der Zee R., Li T., Witzenbichler B., Schatteman G., Isner J. M. (1997). Isolation of putative progenitor endothelial cells for angiogenesis. Science. 275,964-967 https://doi.org/10.1126/science.275.5302.964
  2. Asahara T., Masuda H., Takahashi T., Kalka C., Pastore C., Silver M Kearne M., Magner M., Isner J. M. (1999). Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ. Res. 85, 221-228 https://doi.org/10.1161/01.RES.85.3.221
  3. Boyer M., Townsend L. E., Vogel L. M., Falk .J., Reitz-Vick D., Trevor K. T., Villalba M., Bendick P. J., Glover J. L. (2000). Isolation of endothelial cells and their progenitor cells form human peripheral blood. J. Vase. Surg. 31, 181-189 https://doi.org/10.1016/S0741-5214(00)70080-2
  4. Brooks, P. C., Rosenfeld M., Teisfeld R. A., Hu T., Klier G., Cheresh D. A. (1994). Intergrin alpha v beta 3 antagonists promote tumor regression by induction apopiosis of angiogenic blood vessels. Cell. 79, 1157-1164 https://doi.org/10.1016/0092-8674(94)90007-8
  5. Bussolino, E, Mantovani, A., Persico G. (1997). Molecular mechanisms of blood vessel formation. Trends. Biochem. Sci. 22, 25 J-256
  6. Chaplin, D. J., Pettit G. R., Hill S. A. (1999). Anti-vascular approaches to solid tumor therapy: evaluation of combretastatin A-4 phosphate. Anticancer Res. 19, 189-197 https://doi.org/10.1097/CAD.0b013e3282f3138a
  7. Dark, G. D., Hill, S. A., Prise, V. E., Tozer, G. M., Pettit, G. R., Chaplin, D. J. (1997) Combretastatin A-4, an agent that displays potent and selective toxicity toward tumor vasculature. Cancer Res. 57, 1829-1823
  8. Folkman, J. (1995). Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat. Med. 1, 27-31 https://doi.org/10.1038/nm0195-27
  9. Folkman, J. (1995). Angiogenesis inhibitors generated by tumors. Mol Med. 1, 120-122
  10. Good, D., Polverini, P, Rastinejad, F., Beau M., Lemons, R., Frazier, W., Bouck, N. (1990). A tumor suppressor-dependent inhibitor of angiogenesis is immunologically and functionally indistinguishable from a fragment of thrombospondin, Proc. Natl. Acad. Sci. USA. 87, 6624-6628 https://doi.org/10.1073/pnas.87.17.6624
  11. Jaffe, E. A., Nachman, R. L., Becker, C G., Minick, R. (1973). Culture of human endothelial cells derived from umbilical veins. J. Clin. Invest. 52, 2745-2756 https://doi.org/10.1172/JCI107470
  12. Joe, Y. A., Back, S. H., Park, H. Y., Lee Y. H., Kwon, H. K., Kim Y. J., Lee, S. Y., Seung, K. B., Chae, J. S., Kim, J. H., Hong, S. J., Choi, K. B. (2002). In vitro differentiation of endothelial precursor cells derived from umbilical cord blood. Korean circulation J. 32, 646-654 https://doi.org/10.4070/kcj.2002.32.8.646
  13. Kalka, C., Masuda, H., Takahashi, T., Kalka-Moll W. M., Silver, M., Kearney, M., Li, T., Isner, J. M., Asahara, T (2000) Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization. Proc. Natl. Acad. Sci. 97,3422-3427 https://doi.org/10.1073/pnas.070046397
  14. Kanthou, C. and Tozer, G. M. (2002). The tumor vascular targeting agent combretastain A-4-phosphate induces reorganization fo the actin cytoskeleton and early membrane bleb bing in human endothelial cells. Blood. 99, 2060-2069 https://doi.org/10.1182/blood.V99.6.2060
  15. Moon, H. S., Jacobson E. M., Khersonsky S. M., Luzung, M. R., Walsh, D. P., Siong, W., Lee, J. W., Parikh, P B., Lam, J. C, Kung, T. W., Rosania, G. R, Schier, A. F., Chang, Y. T. (2002). A novel microtubule destabilizing entity form orthogonal synthesis of triazine library and zebrafish embryo screening. J. Am. Chem. Soc. 124, 11608-11609 https://doi.org/10.1021/ja026720i
  16. Murohara, T., Ikeda, H., Duan J., Shintani, S., Sasaki K., Eguchi h., Onitsuka I., Matsui K., Imaizurni T. (2000). Transplanted cord blood-derived endothelial precursor cells augment postnatal neovascularization, J. Clin. Invest. 105, 1527-1536 https://doi.org/10.1172/JCI8296
  17. Nieda, M., Nicol, A., Denning-Kendall P, Sweetenham j., Bradley B., Hows J. (1997). Endothelial cells precursors are normal components of human umbilical cord blood. Br. J. Haematol. 98, 775-777 https://doi.org/10.1046/j.1365-2141.1997.2583074.x
  18. Orelly, M. S., Shing Y, Chen, C., Rosenthal R. A., Moses M., Lane, W. S., Cao, Y., Folkman, J. (1994). Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell. 79. 315-328 https://doi.org/10.1016/0092-8674(94)90200-3
  19. Orclly, M. S., Chen, C., Folkman, J. (1996). Angiostatin induces and sustains dormancy of human primary tumors in mice. Nat.Med. 2. 689-692 https://doi.org/10.1038/nm0696-689
  20. Perez, O. D., Chang, Y. T., Rosania, G., Sutherlin, D., Schultz, P. G. (2002). Inhibition and reversal of myogenic differentiation by purine-based microtubule assembly inhibitors. Chemistry & Biology. 9, 475-483 https://doi.org/10.1016/S1074-5521(02)00131-X
  21. Pettit, G. R., Singh, S. B., Hamel, E., Lin, C. M. Alberts, D. S., Garcia-Kendall D. (1989). Isolation and structure of the strong cell growth and tubulin inhibitor Combrcrastatin A4. Experientia. 45, 205-211 https://doi.org/10.1007/BF01954879
  22. Rafii, S. (2002). Circulating endothelail precursors: mystery, reality, and promise. J. Clin. Invest. 105, 17-19 https://doi.org/10.1172/JCI8774
  23. Rosania, G. R., Chang, Y. T., Perez, O., Sutherlin, D., Dong, H., Lockhart, D. J., Schultz, P. G. (2000). Myosevcrin, a microtubule-binding molecule with novel cellular effects. Nat. Biotechnolo. 18, 304-308 https://doi.org/10.1038/73753
  24. Shintani, S., Murohara, T, Ikeda, H., Ueno, T.,. Honma, T, Katoh, A., Sasaki, K. I. Shimada, T., Oike, Y., Imaizumi, T. (2001). Mobilization of endothelial progenitor cells I patients with acute myocardial infarction. Circulation. 103,2776-2779 https://doi.org/10.1161/hc2301.092122
  25. Tozer, G. M., Prise, V E., Wilson, J., Locke, R. J., Vojnovic, B., Stratford, M. R., Dennis, M. F., Chaplin, D. J. (1999). Combretastatin A-4 phosphate as a tumor vascular targeting agent: early effects in tumors and normal tissues. Cancer. Res. 59, 1626-1633
  26. Voyta, J. C., Via, D. P., Butterfield, C.,E., Zetter, B. R. (1984). Identification and isolation of endothelial cells based on their increased uptake of acetylated-low density lipoprotein. J. Cell. BioI. 99. 2034-2040 https://doi.org/10.1083/jcb.99.6.2034