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Cytotoxicity and apoptosis of benzoquinones: redox cycling, cytochrome c release, and BAD protein expression

  1. Author:
    Tudor, G.
    Gutierrez, P.
    Aguilera-Gutierrez, A.
    Sausville, E. A.

  2. Author Address

    NCI, Dev Therapeut Program, DCTD, EPN 8018,6130 Execut Blvd, Rockville, MD 20852 USA NCI, Dev Therapeut Program, DCTD, Rockville, MD 20852 USA NCI, Sci Applicat Int Corp, Frederick, MD 21702 USA Univ Maryland, Ctr Canc, Baltimore, MD 21201 USA Sausville EA NCI, Dev Therapeut Program, DCTD, EPN 8018,6130 Execut Blvd, Rockville, MD 20852 USA
    1. Year: 2003
  2. Journal: Biochemical Pharmacology
    1. 65
    2. 7
    3. Pages: 1061-1075
  4. Type of Article: Article
  1. Abstract:

    The metabolic activation of a variety of quinone-based anticancer agents occurs, in part, as a result of the bioreductive activation by the flavoprotein NAD(P)H:quinone- acceptor oxidoreductase (NQO1) (EC 1.6.99.2). Using the COMPARE algorithm (http://dtp.nci.nih.gov), a significant statistical correlation has been found in the NCI in vitro anticancer drug screen between high endogenous expression of the pro-apoptotic protein BAD, NQO1 enzymatic activity, and the cytotoxicity of certain antitumor quinones. Two statistically correlated groups of quinones can be discerned: positive-correlated compounds, which are more active in cell lines expressing high baseline levels of BAD protein and NQO1 activity (e.g. the MCF-7 breast carcinoma), and negative-correlated compounds, which are more active in cell lines with undetectable levels of BAD and NQO1 activity (e.g. the HL-60 myeloid leukemia). In the present study, the relationship between quinone structure, redox cycling, and cytotoxicity in the MCF-7 and HL-60 cell lines was investigated. A good biological correlation exists between cytotoxicity and NQO1 activity, BAD protein levels and apoptosis, but not always between cytotoxicity and intracellular reactive oxygen species levels. The overall markedly increased cytotoxicity of the aziridinylbenzoquinone compounds used in this study is accompanied by apoptosis, which occurs mostly through a cytochrome c-independent pathway. (C) 2003 Elsevier Science Inc. All rights reserved.

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