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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

The Identification and Characterization of the Marine Natural Product Scytonemin as a Novel Antiproliferative Pharmacophore

Christopher S. Stevenson, Elizabeth A. Capper, Amy K. Roshak, Brian Marquez, Chris Eichman, Jeffrey R. Jackson, Michael Mattern, William H. Gerwick, Robert S. Jacobs and Lisa A. Marshall
Journal of Pharmacology and Experimental Therapeutics November 2002, 303 (2) 858-866; DOI: https://doi.org/10.1124/jpet.102.036350
Christopher S. Stevenson
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Elizabeth A. Capper
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Amy K. Roshak
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Brian Marquez
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Chris Eichman
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Jeffrey R. Jackson
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Michael Mattern
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William H. Gerwick
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Robert S. Jacobs
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Lisa A. Marshall
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Abstract

Marine natural products provide a rich source of chemical diversity that can be used to design and develop new, potentially useful therapeutic agents. We report here that scytonemin, a pigment isolated from cyanobacteria, is the first described small molecule inhibitor of human polo-like kinase, a serine/threonine kinase that plays an integral role in regulating the G2/M transition in the cell cycle. Scytonemin inhibitedpolo-like kinase 1 activity in a concentration-dependent manner with an IC50 of 2 μM against the recombinant enzyme. Biochemical analysis showed that scytonemin reduced GST-polo-like kinase 1 activity in a time-independent fashion, suggesting reversibility, and with a mixed-competition mechanism with respect to ATP. Although scytonemin was less potent against protein kinase A and Tie2, a tyrosine kinase, it did inhibit other cell cycle-regulatory kinases like Myt1, checkpoint kinase 1, cyclin-dependent kinase 1/cyclin B, and protein kinase Cβ2 with IC50 values similar to that seen forpolo-like kinase 1. Consistent with these effects, scytonemin effectively attenuated, without chemical toxicity, the growth factor- or mitogen-induced proliferation of three cell types commonly implicated in inflammatory hyperproliferation. Similarly, scytonemin (up to 10 μM) was not cytotoxic to nonproliferating endotoxin-stimulated human monocytes. In addition, Jurkat T cells treated with scytonemin were induced to undergo apoptosis in a non-cell cycle-dependent manner consistent with its activities on multiple kinases. Here we propose that scytonemin's dimeric structure, unique among natural products, may be a valuable template for the development of more potent and selective kinase inhibitors used for the treatment of hyperproliferative disorders.

Footnotes

  • This research was funded through the California Sea Grant Program Project E/IF-2 and the National Sea Grant Industrial Fellowship Grant NA66RG0477

  • DOI: 10.1124/jpet.102.036350

  • Abbreviations:
    CDK1
    cyclin-dependent kinase 1
    GST
    glutathione S-transferase
    DTT
    dithiothreitol
    DMSO
    dimethyl sulfoxide
    PBS
    phosphate-buffered saline
    FBS
    fetal bovine serum
    HUVEC
    human umbilical vein endothelial cell
    RSF
    rheumatoid synovial fibroblast
    PDGF
    platelet-derived growth factor
    Sf
    Spodoptera frugiperda
    PAGE
    polyacrylamide gel electrophoresis
    ECGF
    endothelial cell growth factor
    NHLF
    normal human lung fibroblast
    TUNEL
    Terminal deoxynucleotidyl transferase dUTP fluorescein nick-end labeling
    • Received March 18, 2002.
    • Accepted July 16, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 303 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 303, Issue 2
1 Nov 2002
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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

The Identification and Characterization of the Marine Natural Product Scytonemin as a Novel Antiproliferative Pharmacophore

Christopher S. Stevenson, Elizabeth A. Capper, Amy K. Roshak, Brian Marquez, Chris Eichman, Jeffrey R. Jackson, Michael Mattern, William H. Gerwick, Robert S. Jacobs and Lisa A. Marshall
Journal of Pharmacology and Experimental Therapeutics November 1, 2002, 303 (2) 858-866; DOI: https://doi.org/10.1124/jpet.102.036350

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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

The Identification and Characterization of the Marine Natural Product Scytonemin as a Novel Antiproliferative Pharmacophore

Christopher S. Stevenson, Elizabeth A. Capper, Amy K. Roshak, Brian Marquez, Chris Eichman, Jeffrey R. Jackson, Michael Mattern, William H. Gerwick, Robert S. Jacobs and Lisa A. Marshall
Journal of Pharmacology and Experimental Therapeutics November 1, 2002, 303 (2) 858-866; DOI: https://doi.org/10.1124/jpet.102.036350
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