Some Phorbol Esters Might Partially Resemble Bryostatin 1 in their Actions on LNCaP Prostate Cancer Cells and U937 Leukemia Cells

Authors

  • Dr. Noemi Kedei,

    1. Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Building 37, Room 4048B, 37 Convent Drive MSC 4255, Bethesda, MD 20892-4255 (USA), Fax: (+1) 301-496-8709
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  • Emanuel Lubart,

    1. Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Building 37, Room 4048B, 37 Convent Drive MSC 4255, Bethesda, MD 20892-4255 (USA), Fax: (+1) 301-496-8709
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  • Nancy E. Lewin,

    1. Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Building 37, Room 4048B, 37 Convent Drive MSC 4255, Bethesda, MD 20892-4255 (USA), Fax: (+1) 301-496-8709
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  • Dr. Andrea Telek,

    1. Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Building 37, Room 4048B, 37 Convent Drive MSC 4255, Bethesda, MD 20892-4255 (USA), Fax: (+1) 301-496-8709
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  • Langston Lim,

    1. Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892 (USA)
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  • Poonam Mannan,

    1. Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892 (USA)
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  • Dr. Susan H. Garfield,

    1. Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892 (USA)
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  • Matthew B. Kraft,

    1. Department of Chemistry, University of Utah, Salt Lake City, UT 84112 (USA)
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  • Prof. Dr. Gary E. Keck,

    1. Department of Chemistry, University of Utah, Salt Lake City, UT 84112 (USA)
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  • Dr. Sofiya Kolusheva,

    1. Department of Chemistry, Ben Gurion University, Beer Sheva 84105 (Israel)
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  • Prof. Dr. Raz Jelinek,

    1. Department of Chemistry, Ben Gurion University, Beer Sheva 84105 (Israel)
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  • Dr. Peter M. Blumberg

    Corresponding author
    1. Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Building 37, Room 4048B, 37 Convent Drive MSC 4255, Bethesda, MD 20892-4255 (USA), Fax: (+1) 301-496-8709
    • Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Building 37, Room 4048B, 37 Convent Drive MSC 4255, Bethesda, MD 20892-4255 (USA), Fax: (+1) 301-496-8709
    Search for more papers by this author

Abstract

Phorbol 12-myristate 13-acetate (PMA) and bryostatin 1 are both potent protein kinase C (PKC) activators. In LNCaP human prostate cancer cells, PMA induces tumor necrosis factor alpha (TNFα) secretion and inhibits proliferation; bryostatin 1 does not, and indeed blocks the response to PMA. This difference has been attributed to bryostatin 1 not localizing PKCδ to the plasma membrane. Since phorbol ester lipophilicity influences PKCδ localization, we have examined in LNCaP cells a series of phorbol esters and related derivatives spanning some eight logs in lipophilicity (logP) to see if any behave like bryostatin 1. The compounds showed marked differences in their effects on proliferation and TNFα secretion. For example, maximal responses for TNFα secretion relative to PMA ranged from 97 % for octyl-indolactam V to 24 % for phorbol 12,13-dibenzoate. Dose–response curves ranged from monophasic for indolactam V to markedly biphasic for sapintoxin D. The divergent patterns of response, however, correlated neither to lipophilicity, to plasma membrane translocation of PKCδ, nor to the ability to interact with model membranes. In U937 human leukemia cells, a second system in which PMA and bryostatin 1 have divergent effects, viz. PMA but not bryostatin 1 inhibits proliferation and induces attachment, all the compounds acted like PMA for proliferation, but several induced a reduced level or a biphasic dose–response curve for attachment. We conclude that active phorbol esters are not all equivalent. Depending on the system, some might partially resemble bryostatin 1 in their behavior; this encourages the concept that bryostatin-like behavior may be obtained from other structural templates.

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