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, P56lck, 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 P56lck PTK activityin vitro and can mediate such actionin vivo.
Similar content being viewed by others
References Cited
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).
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).
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).
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).
Bishop, J. M., The molecular genetics of cancer.Science, 235, 305–311 (1987).
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).
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).
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).
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).
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).
Hunter, T. and Cooper, J. A., Protein tyrosine kinase.Annu. Rev. Biochem., 54, 897–930 (1985).
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).
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).
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).
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).
Levitzki, A., Tyrphostins: potential antiproliferative agents and novel molecular tools.Biochem. Pharmacol., 40, 313–319 (1990).
Levizki, A., Grazit, A., Osherov, N., Posner, I. and Gilon, C., Inhibition of protein-tyrosine kinases by tyrphostins.Meth. Enzymol., 201, 347–361 (1991).
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).
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).
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).
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).
Ross, R., The pathogenic of atherosclerosis: an update.N. Engl. J. Med., 314, 488–500 (1986).
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).
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).
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).
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).
Ullrich, A. and Schlessinger, J., Signal transduction by receptor with tyrosine kinase activity.Cell, 61, 203–212 (1990).
Umezawa, K. and Imoto, M., Use of erbstatin as protein-tyrosine kinase inhibitor.Methods Enzymol., 201, 379–380 (1991).
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).
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).
Yarden, Y. and Ullrich, A., Growth factor receptor tyrosine kinases.Annu. Rev. Biochem., 57, 443–478 (1988).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Kil, KS., Yum, YN., Seo, SH. et al. Antitumor activities of hypericin as a protein tyrosine kinase blocker. Arch. Pharm. Res. 19, 490–496 (1996). https://doi.org/10.1007/BF02986017
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF02986017