Protein Kinase C Inhibition by ET-18-OCH3 and Related Analogs

A Target for Cancer Chemotherapy
  • Susan B. Pauig
  • Lary W. Daniel
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 416)


Protein kinase C (PKC), is an important component of signal transduction mechanisms involving many physiological and pharmacological agonists1. While many isoforms are known2,3, those isoforms which are responsive to the phorbol ester, TPA4, and the lipid second messenger, diacylglycerol (DAG)5 are the most completely characterized. PKC activation is a necessary component for TPA induced differentiation of the human acute myelogenous leukemia cell line, HL-606–9. However, PKC activation does not appear to be required for tumor necrosis factor α (TNFα) induced differentiation10. PKC may be involved in differentiation induced by vitamin D3 and all-trans retinoic acid, since both cause upregulation of PKC isozyme levels11,12. Differentiation induction therapy provides an alternative therapeutic approach for patients with acute myeloid leukemia (AML) who are either unsuitable for or unreponsive to conventional cytotoxic chemotherapy13,14.


Acute Myeloid Leukemia Phorbol Ester Ether Lipid Monocytic Differentiation Phorbol Diester 
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  1. 1.
    Blumberg, P.M., Aces, G., Areces, L.B., Kazanietz, M.G., Lewin, N.E., and Szallasi, Z. Protein kinase C in signal transduction and carcinogenesis. In: Receptor-Mediated Biological Processes: Implications for Evaluating Carcinogenesis, pp. 3–19, Wiley-Liss, Inc.. 1994.Google Scholar
  2. 2.
    Kikkawa, U., Kishimoto, A., and Nishizuka, Y. The protein kinase C family: heterogeneity and its implications. Ann. Rev. Biochem., 58: 31–44, 1989.PubMedCrossRefGoogle Scholar
  3. 3.
    Parker, P.J., Kour, G., Marais, R.M., Mitchell, F., Pears, C., Schaap, D., Stabel, S., and Webster, C. Protein kinase C-a family affair. Mol. Cell. Endo., 65: 1–11, 1989. Google Scholar
  4. 4.
    Castagna, M., Takai, Y., Kaibuchi, K., Sano, K., Kikkawa, U., and Nishizuka, Y. Direct activation of calcium-activated, phospholipid-dependent protein kinase by tumour-promoting phorbol esters. J. Biol. Chem., 257: 7847–7851, 1982.PubMedGoogle Scholar
  5. 5.
    Kishimoto, A., Takai, Y., Mori, T., Kikkawa, U., and Nishizuka, Y. Activation of calcium and phospholipiddependent protein kinase by diacylglycerol, its possible relation to phosphatidylinositol turnover. J. Biol. Chem., 255: 2273–2276, 1980.PubMedGoogle Scholar
  6. 6.
    Kiss, Z., Deli, E., and Kuo, J.F. Temporal changes in intracellular distribution of protein kinase C during differentiation of human leukemia HL-60 cells induced by phorbol ester. FEBS Letters, 231: 41–46, 1988.PubMedCrossRefGoogle Scholar
  7. 7.
    Nishikawa, M., Komada, F., Uemura, Y., Hidaka, H., and Shirakawa, S. Decreased expression of type II protein kinase C in HL-60 variant cells resistant to induction of cell differentiation by phorbol diester. Cancer Research, 50: 621–6626, 1990.PubMedGoogle Scholar
  8. 8.
    Nakaki, T., Mita, S., Yamamoto, S., Nakadate, T., and Kato, R. Inhibition by palmitoylcarnitine of adhesion and morphological changes in HL-60 cells induced by 12-O-tetradecanoylphorbol-13-acetate. Cancer Research, 44: 1908–1912, 1984.PubMedGoogle Scholar
  9. 9.
    Macfarlane, D.E. and Manzel, L. Activation of (3-isozyme of protein kinase C (PKCI3) is necessary and sufficient for phorbol ester-induced differentiation of HL-60 promyelocytes. J. Biol. Chem., 269: 4327–4331, 1994.PubMedGoogle Scholar
  10. 10.
    Chedid, M., Yoza, B.K., Brooks, J.W., and Mizel, S.B. Activation of AP-1 by IL-1 and phorbol esters in T cells. Role of protein kinase A and protein phosphatases. J. Immunology, 147: 867–873, 1991.Google Scholar
  11. 1l.
    Obeid, L.M., Okazaki, T., Karolak, L.A., and Hannun, Y.A. Transcriptional regulation of protein kinase C by 1,25-dihydroxyvitamin D3 in HL-60 cells. J. Biol. Chem., 265: 2370–2374, 1990.PubMedGoogle Scholar
  12. 12.
    Makowski, M., Ballester, R., Cayre, V., and Rosen, O.M. Immunochemical evidence that three protein kinase C isozymes increase in abundance during HL-60 differentiation induced by dimethyl sulfoxide and retinoic acid. J. Biol. Chem., 163: 3402–3410, 1988.Google Scholar
  13. 13.
    Hassan, H.T. Differentiation induction of therapy of acute myelogenous leukemias. Haematologia, 21: 141–150, 1988.PubMedGoogle Scholar
  14. 14.
    Hassan, H.T. Differentiation induction therapy: An alternative for the treatment of elderly patients with acute myelogenous leukemias. J. Clin. Exp. Gerontology„ 10: 63–73, 1988.Google Scholar
  15. 15.
    Obeid, L.M., Linardic, C.M., Karolak, L.A., and Hannun, Y.A. Programmed cell death induced by ceramide. Science, 259: 1769–1771, 1993.PubMedCrossRefGoogle Scholar
  16. 16.
    Jarvis, W.D., Fornari, F.A., Browning, J.L., Gewirtz, D.A., Kolesnick, R.N., and Grant, S. Attenuation of ceramide-induced apoptosis by diglyceride in human myeloid leukemia cells. J. Biol. Chem., 269: 31685–31692, 1994.PubMedGoogle Scholar
  17. 17.
    Jarvis, W.D., Povirk, L.F., Turner, A.J., Traylor, R.S., Gewirtz, D.A., Pettit, G.R., and Grant, S. Effects of bryostatin 1 and other pharmacological activators of protein kinase C on 1-[ß-D-arabinofuranosyl]cytosine-induced apoptosis in HL-60 human promyelocytic leukemia cells. Biochemical Pharmacology, 47: 839–852, 1994.CrossRefGoogle Scholar
  18. 18.
    Jarvis, W.D., Turner, A.J., Povirk, L.F., Traylor, R.S., and Grant, S. Induction of apoptotic DNA fragmentation and cell death in HL-60 human promyelocytic leukemia cells by pharmacological inhibitors of protein kinase C. Cancer Research, 54: 1707–1714, 1994.PubMedGoogle Scholar
  19. 19.
    Berdel, G.E. Ether lipids and derivatives as investigational anticancer drugs. Onkologie, 13: 245–250, 1990.CrossRefGoogle Scholar
  20. 20.
    Berdel, W.E. Membrane-interactive lipids as experimental anticancer drugs. British Journal of Cancer, 64: 208–211, 1991.PubMedCrossRefGoogle Scholar
  21. 21.
    Honma, Y., Kasukabe, T., Hozumi, M., Tsushima, S., and Nomura, H. Induction of differentiation of cultured human and mouse myeloid leukemia cells by alkyl-lysophospholipids. Cancer Research, 41: 3211–3216, 1981.PubMedGoogle Scholar
  22. 22.
    Rogers, M.A., Samples, L., Chabot, M.C., Marasco, C.J., Piantadosi, C., and Daniel, L.W. Leukemic cell differentiation by ether-linked lipids: studies on quartemary ammonium alkylglycerols. Proceedings of the American Association for Cancer Research, 31: 410, 1990.Google Scholar
  23. 23.
    Diomede, L., Colotta, F., Piovani, B., Re, F., Modest, E.J., and Salmona, M. Induction of apoptosis in human leukemic cells by the ether lipid 1-O-octadecyl-2-methyl-rac-glycero-3-phosphocholine: a possible basis for its selective action. Internationl Journal of Cancer, 53: 124–130, 1993.CrossRefGoogle Scholar
  24. 24.
    Diomede, L., Piovani, B., Re, F., Principe, P., Colotta, F., and Modest, E.J. The induction of apoptosis is a common feature of the cytotoxic action of ether-linked glycerophospholipids in human leukemic cells. International Journal of Cancer, 57: 645–649, 1994.CrossRefGoogle Scholar
  25. 25.
    Vogler, W.R., Berdel, W.E., Olson, A.C., Winton, E.F., Heffner, L.T., and Gordon, D.S. Autologous bone marrow transplantation in acute leukemia with marrow purged with alkyl-lysophospholipid. Blood, 80: 1423–1429, 1992.Google Scholar
  26. 26.
    Hoffman, D.R., Hoffman, L.H., and Snyder, F. Cytotoxicity and metabolism of alkyl phospholipid analogues in neoplastic cells. Cancer Research, 46: 5803–5809, 1986.Google Scholar
  27. 27.
    Wilcox, R.W., Wykle, R.L., Schmitt, J.D., and Daniel, L.W. The degradation of platelet activating factor and related lipids: susceptibility to phospholipases C and D. Lipids, 22: 800–807, 1987.PubMedCrossRefGoogle Scholar
  28. 28.
    Daniel, L.W., Small, G.W., and Strum, J.C. Characterization of cells sensitive and resistant to ET-18OCH3. Proceedings of the American Association for Cancer Research, 31: 412, 1990.Google Scholar
  29. 29.
    Chabot, M.C., Wykle, R.L., Modest, E.J., and Daniel, L.W. Correlation of ether lipid content of human leukemia cell lines and their susceptibility to 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine. Cancer Research, 49: 4441–4445, 1989.PubMedGoogle Scholar
  30. 30.
    Diomede, L., Bizzi, A., Magistrelli, A., Modest, E.J., Salmona, M., and Noseda, A. Role of cell cholesterol in modulating antineoplastic ether lipid uptake, membrane effects, and cytotoxicity. International Journal of Cancer, 46: 341–346, 1990.CrossRefGoogle Scholar
  31. 31.
    Daniel, L.W. Ether lipids in experimental cancer chemotherapy. In: J.A. Hickman and T.R. Tritton (eds.), Cancer Chemotherapy, pp. 146–178, Oxford: Blackwell Scientific Publications. 1993.Google Scholar
  32. 32.
    Helfman, D.M., Barnes, K.C., Kinkade, J.M.Jr, Vogler, W.R., Shoji, M., and Kuo, J.F. Phospholipid-sensitive Ca2.-dependent protein phosphorylation system in various types of leukemic cells from human patients and in human leukemic cell lines HL60 and K562, and its inhibition by alkyl-lysophospholipid. Cancer Research, 43: 2955–2961, 1983.PubMedGoogle Scholar
  33. 33.
    Parker, J., Daniel, L.W., and Waite, M. Evidence of protein kinase C invovlement in phorbol diester-stimulated arachidonic acid release and prostaglandin synthesis. J. Biol. Chem., 262: 5385–5393, 1987.PubMedGoogle Scholar
  34. 34.
    Shoji, M., Raynor, R.L., Berdel, W.E., Vogler, W.R., and Kuo, J.F. Effects of thioether phospholipid BM41.440 on protein kinase C and phorbol ester-induced differentiation of human leukemia HL-60 and KG-1 cells. Cancer Research, 48: 6669–6673, 1988.PubMedGoogle Scholar
  35. 35.
    Berdel, W.E., Fromm, M., Fink, U., Pahlke, W., Bicker, U., Reichert, A., and Rastetter, J. Cytotoxicity of thioether-lysophospholipids in leukemia and tumours of human origin. Cancer Research, 43: 5538–5543, 1983.Google Scholar
  36. 36.
    Daniel, L.W., Etkin, L.A., Morrison, B.T., Parker, J., Morris-Natschke, S., Surles, J.R., and Piantadosi, C. Ether lipids inhibit the effects of phorbol diester tumor promoters. Lipids, 22: 851–855, 1987.PubMedCrossRefGoogle Scholar
  37. 37.
    Daniel, L.W. Protein kinase C inhibition by alkyl-linked lipids. In: J.J. Kabara (ed.), The Pharmacological Effects of Lipids, pp. 90–96, Illinois: The American Oil Chemists Society. 1990.Google Scholar
  38. 38.
    Rogers, M.A., Small, G.W., Samples, L., and Daniel, L.W. Phorbol diester stimulated HL-60 cell differentiation is associated with the activation of specific DNA binding proteins. Proceedings of the American Association for Cancer Research, 32: 295, 1991.Google Scholar
  39. 39.
    Kiss, Z., Deli, E., Vogler, W.R., and Kuo, J.F. Antileukemic agent alkyl-lysophospholipid regulates phosphorylation of distinct proteins in HL-60 and K562 cells and differentiation of HL-60 cells promoted by phorbol ester. Biochemical Biophysical Research Communications, 142: 661–666, 1987.CrossRefGoogle Scholar
  40. 40.
    Frei, E., Bickers, J.N., Hewitt, M., Leary, W.V., and Talley, R.W. Dose schedule and antitumor studies of arabinosyl cytosine. Cancer Research, 29: 1325–1332, 1969.PubMedGoogle Scholar
  41. 41.
    Hassan, H.T. and Rees, J.K. Triple Combination of Retinoic acid + low concentration of cytosine arabinoside + hexamethylene bisacetamide induces differentiation of human AML blasts in primary culture. Hematological Oncology, 7: 429–440, 1989.PubMedCrossRefGoogle Scholar
  42. 42.
    Hassan, H.T. and Rees, J.K. Low concentrations of cytosine arabinoside, 6-thioguanine, actinomycin-D and aclacinomycin A stimulate the differentiation of normal human marrow myeloid progenitor cells. Medical Oncology & Tumor Pharamcotherapy, 6: 213–217, 1989.Google Scholar
  43. 43.
    Nino, K. and Nakamaki, T. Differentiation therapy for myelodysplastic syndrome. Japanese Journal of Clinical Hematology, 34: 283–288, 1993.Google Scholar
  44. 44.
    Brach, M.A., Mertelsmann, R.H., and Herrmann, F. Modulation of cytotoxicity and differentiation-inducing potential of arabinofuranosylcytosine in myeloid leukemia cells by hematopoietic cytokines. Cancer Investigation, II: 198–211, 1993.Google Scholar
  45. 45.
    Strum, J.C., Small, G.W., Pauig, S.B., and Daniel, L.W. 1–43-D-arabinofuranosylcytosine stimulates ceramide and diglyceride formation in HL-60 cells. J. Biol. Chem., 269: 15493–15497, 1994.Google Scholar
  46. 46.
    Kharbanda, S., Datta, R., and Kufe, D. Regulation of c-jun gene expression in HL-60 leukemia cells by 113-D-arabinofuranosylcytosine. Biochemistry, 30: 7947–7952, 1991.CrossRefGoogle Scholar
  47. 47.
    Kharbanda, S., Emoto, Y., Kisaki, H., Saleem, A., and Kufe, D. 1-beta D-arabinofuranosylcytosine activates serine/threonine protein kinases and c-jun gene expression in phorbol ester-resistant myeloid leukemia cells. Molecular Pharmacology, 46: 67–72, 1994.Google Scholar
  48. 48.
    Ueda, T., Imamura, S., and Kawai, Y. Successful treatment of myelodysplastic syndrome with 1–13-Darabinofuranosylcytosine-5’-stearyl phosphate. Leukemia Research, 14: 1067, 1990.PubMedCrossRefGoogle Scholar
  49. 49.
    Aquino, A., Hartman, K.D., Knode, M.C., Grant, S., Huang, K.P., Niu, C.H., and Glazer, R.I. Role of protein kinase C in phosphorylation of vinculin in adriamycin resistant HL-60 leukemia cells. Cancer Research, 48: 3324–3329, 1988.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1996

Authors and Affiliations

  • Susan B. Pauig
    • 1
  • Lary W. Daniel
    • 1
  1. 1.Department of Biochemistry Bowman Gray School of MedicineWake Forest UniversityWinston-SalemUSA

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