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Antitumor activities of hypericin as a protein tyrosine kinase blocker

  • Kwang-Sup Kil
  • Young-Na Yum
  • Seung-Hoon Seo
  • Kyung-Tae Lee
Research Articles

Abstract

Naphtodianthrone hypericin produced a potent antitumor activityin vitro against several tumor cells. However, it did not show any cytotoxicity on normal cells such asMacaccus rheus monkey kidney cells (MA-104) and primary cultured rat hepatocytes up to 500 μM concentration. Hypericin added to A431 human epidermoid carcinoma cell membrane inhibited the autophosphorylation of the epidermal growth factor (EGF) receptor and the tyrosine phosphorylation of RR-SRC peptide catalyzed by an EGF-receptor. Similarly, treatment of the A431 cells with hypericin inhibited the tyrosine phosphorylation of EGF-dependent endogenous EGF-receptor by western blotting analysis. Hypericin also inhibited the T cell PTK, P56 lck , in a dose-dependent fashion with an IC50=5 μM. The tyrosine phosphorylation on RR-SRC peptide and EGF-induced receptor autophosphorylation, eitherin vitro or in intact cells was inhibited by hypericin at the same concentration as that in A431 cell proliferation. These data suggest that hypericin directly inhibits EGF-receptor and P56 lck PTK activityin vitro and can mediate such actionin vivo.

Key words

Hypericin Protein tyrosine kinase P56lck Epidermal growth factor Cytotoxicity RR-SRC peptide 

References Cited

  1. Akiyama, T., Ishida, J., Nakagawa, S., Ogawara, H., Watanabe, S. I., Itoh, N., Shibuya, M. and Fukami, Y., Genistein, a specific inhibitor of tyrosine-specific protein kinases.J. Biol. Chem., 262, 5592–5595 (1987).PubMedGoogle Scholar
  2. Baek, S. H., Han, D. S., Yook, C. N., Kim, Y. C. and Kwak, J. S., Synthesis and antitumor activity of Cannabigerol.Arch. Pharm. Res., 19, 228–230 (1996).CrossRefGoogle Scholar
  3. Basler, K. and Haften, E., Control of phosphoreceptor cells fate by the sevenless protein requires a functional tyrosine kinase domain.Cell, 54, 299–311 (1988).PubMedCrossRefGoogle Scholar
  4. Bertics, P. J. and Gill, G. N., Self-phosphorylation enhances the protein-tyrosine kinase activity of the epidermal growth factor receptor.J. Biol. Chem., 206, 14642–14647 (1985).Google Scholar
  5. Bishop, J. M., The molecular genetics of cancer.Science, 235, 305–311 (1987).PubMedCrossRefGoogle Scholar
  6. Cohen, D. I., Tani, Y., Tian, H., Boone, E., Samelson, L. E. and Lane, H. C., Participation of tyrosine phosphorylation in the cytopathic effect of human immunodeficiency virus-1.Science, 256, 542–545 (1992).PubMedCrossRefGoogle Scholar
  7. Denizot, F. and Lang, R., Rapid colorimetric assay for cell growth and survival: modifications to the tetrazolium dye procedure giving improved sensitivity and reliability.J. Immun. Methods., 89, 271–277 (1986).CrossRefGoogle Scholar
  8. Filvaroff, E., Stern, D. F. and Dotto, G. P., Tyrosine phosphorylation is an early and specific event involved in primary keratinocyte differentiation.Mol. Cell. Biol., 10, 1164–1173 (1990).PubMedGoogle Scholar
  9. Fukazawa, H., Li, P-M, Yamamoto, C., Murakami, Y., Mizuno, S. and Uehara, Y., Specific inhibition of cytoplasmic protein tyrosine kinases by herbimycin Ain vitro.Biochem. Pharmacol., 42, 1661–1667 (1991).PubMedCrossRefGoogle Scholar
  10. Geissler, J. F., Traxler, P., Regenass, U., Murray, B. J., Roesel, J. L., Meyer, T., McGlynn, E., Storni, A. and Lydon, N.B., Thiazolidine-diones: biochemical and biological activity of a novel class of tyrosine protein kinase inhibitors.J. Biol. Chem., 265, 22255–22261 (1990).PubMedGoogle Scholar
  11. Hunter, T. and Cooper, J. A., Protein tyrosine kinase.Annu. Rev. Biochem., 54, 897–930 (1985).PubMedGoogle Scholar
  12. Hsuan, J. J., Panayotou, G. and Waterfield, M. D., Structural basis for epidermal growth factor receptor function.Progress in Growth factor Research, 1, 23–32 (1989).PubMedCrossRefGoogle Scholar
  13. Kim, Y. S., Evidence for regulation of interaction of endogenous protein kinase C substrate with plasma membrane by PKC down-regulation in K562 cells.Arch. Pharm. Res., 18, 301–307 (1995).CrossRefGoogle Scholar
  14. Lavie, G., Valentine, F., Levine, B., Mazur, Y., Galo, G., Lavie, D., Weiner, D. and Meruelo, D., Studies of the mechanisms of the action of the antiretroviral agents hypericin and pseudohypericin.Proc. Natl. Acad. Sci. USA, 86, 5963–5967 (1989).PubMedCrossRefGoogle Scholar
  15. Lee, K. T., Vandenberghe, Y., Herin, M., Cavalier, R., Beck, D., Li, A., Vrebeke, N. and Roba, J. Comparative metabolism of SC-42867 and SC-51089, two PGE2 antagonist, in rat and human hepatocyte cultures.Xenobiotica, 24, 25–36 (1994).PubMedCrossRefGoogle Scholar
  16. Levitzki, A., Tyrphostins: potential antiproliferative agents and novel molecular tools.Biochem. Pharmacol., 40, 313–319 (1990).CrossRefGoogle Scholar
  17. Levizki, A., Grazit, A., Osherov, N., Posner, I. and Gilon, C., Inhibition of protein-tyrosine kinases by tyrphostins.Meth. Enzymol., 201, 347–361 (1991).CrossRefGoogle Scholar
  18. Lifson, J. D., Feinberg, M. B., Reyes, G.R., Rabin, L., banapour, B., Chakrabarti, S., Moss, B., Wong-Staal, F., Steimer, K. S. and Engleman, E. G., Induction of CD4-dependent cell fusion by the HTLV-III/LAV envelope glycoprotein.Nature, 323, 725–728 (1986).PubMedCrossRefGoogle Scholar
  19. Lyall, R.M., Zilberstein, A., Gazit, A., Gilon, C., Levizki, A. and Schlessinger, J., Tyrphostins inhibit epidermal growth factor (EGF)-receptor tyrosine kinase activity in living cells and EGF-stimulated cell proliferation.J. Biol. Chem., 264, 14503–14509 (1989).PubMedGoogle Scholar
  20. Meruelo, D., Lavie, G. and Lavie, D., Therapeutic agents with dramatic antiretroviral activity and little toxicity at effective dose: Aromatic polycyclic diones hypericin and pseudohypericin.Proc. Natl. Acad. Sci. USA., 85, 5230–5234 (1988).PubMedCrossRefGoogle Scholar
  21. Murakami, Y., Mizuno, S., Hori, M. and Uehara, Y., Reversal of transformed phenotypes by herbimycin A in src oncogene expresses rat fibroblasts.Cancer Res., 48, 1587–1590 (1988).PubMedGoogle Scholar
  22. Ross, R., The pathogenic of atherosclerosis: an update.N. Engl. J. Med., 314, 488–500 (1986).PubMedGoogle Scholar
  23. Secrist, J. P., Sehgal, I., Poeis, G. and Abraham, R. T., Preferential inhibition of the platelet-derived growth factor receptor tyrosine kinases by staurosporine.J. Biol. Chem., 265, 20394–20400 (1990).PubMedGoogle Scholar
  24. Tang, J., Colacino, J. M., Larsen, S. H. and Spitzer, W., Virucidal activity of hypericin against enveloped and non-enveloped DNA and RNA viruses.Antiviral Res., 13, 313–326 (1990).PubMedCrossRefGoogle Scholar
  25. Thom, D., Powel, A. J., Lloyd, C. W. and Rees, D. A., Rapid isolation of plasma membranes in high yield from culture fibroblast.Biochem. J., 168, 187–194 (1977).PubMedGoogle Scholar
  26. Trevillyan, J., Lu, Y., Atluru, D., Phillips, C. and Bjorndahl, J., Differential inhibition of T cell receptor signal transduction and early activation events by a selective inhibitor of protein tyrosine kinase.J. Immunol., 145, 3223–3228 (1990).PubMedGoogle Scholar
  27. Ullrich, A. and Schlessinger, J., Signal transduction by receptor with tyrosine kinase activity.Cell, 61, 203–212 (1990).PubMedCrossRefGoogle Scholar
  28. Umezawa, K. and Imoto, M., Use of erbstatin as protein-tyrosine kinase inhibitor.Methods Enzymol., 201, 379–380 (1991).PubMedCrossRefGoogle Scholar
  29. Weissman, B. and Aaronson, S. A., Members of the src and ras oncogene families supplant the epidermal growth factor requirement of BALB/MK-2 keratinocytes and induce, distinct alternation in their terminal differentiation.Mol. Cell. Biol., 5, 3386–3396 (1985).PubMedGoogle Scholar
  30. Yaish, P., Gazit, A., Gilon, C. and Levitzki, A., Blocking of EGF dependent cell proliferation by EGF receptor kinase inhibitors.Science, 242, 933–935 (1988).PubMedCrossRefGoogle Scholar
  31. Yarden, Y. and Ullrich, A., Growth factor receptor tyrosine kinases.Annu. Rev. Biochem., 57, 443–478 (1988).PubMedCrossRefGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea 1996

Authors and Affiliations

  • Kwang-Sup Kil
    • 1
  • Young-Na Yum
    • 1
  • Seung-Hoon Seo
    • 2
  • Kyung-Tae Lee
    • 2
  1. 1.Department of Pathology, Institute of ToxicologyKorea FDASeoulKorea
  2. 2.College of PharmacyKyung Hee UniversitySeoulKorea

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