Abstract
Hypericin, a photosensitizing plant pigment, was found to be a potent inducer of differentiation of human myeloid leukemia U-937 cells. At a concentration of 0.2 µM, hypericin exhibited 50% growth inhibition. An effect on cell differentiation by hypericin was assessed by its ability to induce phagocytosis of latex particles, and to reduce nitroblue tetrazolium (NBT). Approximately 51% of 0.2 µM hypericin-treated cells were stained with NBT and 63% showed phagocytic activity. In order to establish whether hypericin induces differentiation of U-937 cells to macrophage or granulocyte, esterase activities and cell sizes were measured. When U-937 cells were treated with 0.2 µM and 0.15 µM of hypericin, the α-naphthyl acetate esterase activity was increased by 38.4% and 48.1%, respectively, but naphthol AS-D chloroacetate esterase activity was not influenced. The size of hypericin-treated cells in terms of cell mass was larger than that observed in untreated cells as determined by flow cytometry. Protein kinase C (PKC) inhibitor, NA-382, decreased the NBT reducing activity of hypericin, whereas a cAMP-dependent protein kinase A (PKA) inhibitor, H-89, did not show any influence on the differentiation. These results indicate that hypericin triggers differentiation toward monocyte/macrophage lineage by PKC stimulation.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References Cited
Agostinis, P., Vandenbogaerde, A., Donella-deana, A., Pinna, L. A., Lee, K. T., Goris, J., Merlevede, W., Vandenheede, J. R. and De Witte, P., Photosensitized inhibition of growth factor regulated protein kinase by hypericin.Biochem. Pharmacol., 49, 1615–1622 (1995).
Breitman, T. R., Selonick, S. E. and Collins, S. J., Induction of differentiation of the human promyelocytic cell line by retinoic acid.Proc. Natl. Acad. Sci. USA, 77, 2936–2940 (1980).
Cho-Chung, Y. S. and Clair, T., The regulatory subunit of cAMP-dependent protein kinase as a target for chemotherapy of cancer and other cellular dysfunctional-related diseases.Pharmacol. Then, 60, 265–288 (1993).
Chomienne, C., Fenaux, P. and Degos, L., Retinoid differentiation therapy in promyelocytic leukemia.FASEB. J, 10, 1025–1930 (1996).
Collins, S. J., Ruscetti, F. W., Gallagher, R. E. and Gallo, R. C., Terminal differentiation of human promyelocytic leukemia cells induced by dimethylsulfoxide and other polar compounds,Proc. Natl. Acad. Sci. USA, 75, 2458–2462 (1978).
Denning, M. F., Dlugosz, A. A., Threadgill, D. W., Magnuson, T. and Yuspa, S. H., Activation of the epidermal growth factor receptor signal transduction pathways stimulate tyrosine phosphorylation of protein kinase C5.J. Biol. Chem., 271, 5325–5331 (1996).
Harris, P. E., Ralph, P., Gabriloveo, J., Welte, K., Karmali, R. and Moore, M. A. S., Distinct differentiation inducing activities of γ-interferon and cytokine factors acting on the human promyelocytic leukemia cell line HL 60.Cancer Res., 45, 3090–3095 (1985).
Kil, K. S., Yum, Y. N., Seo, S. H. and Lee, K. T., Antitumor activities of hypericin as a protein tyrosine kinase blocker.Arch. Pharm. Res., 19, 490–496 (1996).
Meruelo, D. and Lavie, C., Therapeutic agents with dramatic antiretroviral activity and little toxicity at effective doses: aromatic polycyclic diones hypericin and pseudohypericin.Proc. Natl. Acad. Sci. USA, 85, 5230–5234 (1988).
Kondo, K., Watanabe, T., Sasaki, H., Uehara, Y. and Oishi, M., Induction ofin vitro differentiation of mouse embryonal carcinoma(F9) and erythroleukemia (MEL) cells by herbimycin A, an inhibitor of protein phosphorylation.Mol. Cell Biol., 7, 285–293 (1989).
Miyaura, C., Abe, E., Kuribayashi, T., Tanaka, H., Konno, K., Nishii, Y. and Suda, T., 1α25-Dihydroxyvi-tamin D3 induces differentiation of human myeloid cells.Biochem. Biophys. Res. Commun., 102, 937–943 (1981).
Rovera, G., Santoli, K. and Damsky, C, Human promyelocytic leukemia cell in culture differentiates into macrophage-like cells when treated with phorbol diesters.Proc. Natl. Acad Sci. USA, 76, 2799–2783 (1979).
Sandrostrom, C. and Vilsson, K., Establishment and characterization of a human histocytic cell line.Int. J. Cancer, 17, 565–577 (1976).
Takahashi, I. and Nakanishi, S., Hypericin and pseudohypericin speciality inhibit protein kinase C: Possible relation to their antiretroviral activity.Biochem. Biophys. Res. Commun., 165, 1207–1212 (1989).
Ways, D. K., Messer, B. R., Garris, T. O., Qin, W., Cook, P. P. and Parker, P. P., Modulation of protein kinase C by phobol esters in monoblast U937 cell.Cancer Res., 52, 5604–5609 (1992).
Zhang, W., Hinton, D. R., Surnock,A. A. and Couldwell, W. T., Malignant glioma sensitivity to radiotherapy, high-dose tamoxifen and hypericin: corroborating clinical responsein vitro: case report.Neurosurgery, 38, 587–591 (1996).
Zhang, L., Nakaya, K., Yoshida, T. and Kuroiwa, Y., Induction by bufalin of human leukemia cells HL 60, U937 and ML1 toward macrophage/monocyte-like cells and its potent synergistic effect on the differentiation of human leukemia cells in combination with other inducers.Cancer Res., 52, 4634–4641 (1992).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Kim, JI., Park, JH., Park, HJ. et al. Induction of differentiation of the human histocytic lymphoma cell line U-937 by hypericin. Arch. Pharm. Res. 21, 41–45 (1998). https://doi.org/10.1007/BF03216751
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF03216751