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DNA Methyltransferase Inhibitor, Zebularine, Delays Tumor Growth and Induces Apoptosis in a Genetically Engineered Mouse Model of Breast Cancer

  1. Author:
    Chen, M.
    Shabashvili, D.
    Nawab, A.
    Yang, S. X.
    Dyer, L. M.
    Brown, K. D.
    Hollingshead, M.
    Hunter, K. W.
    Kaye, F. J.
    Hochwald, S. N.
    Marquez, V. E.
    Steeg, P.
    Zajac-Kaye, M.

  2. Author Address

    [Zajac-Kaye, Maria] Univ Florida, Coll Med, Dept Anat & Cell Biol, Gainesville, FL 32610 USA. [Chen, Min; Kaye, Frederic J.; Zajac-Kaye, Maria] Univ Florida, Dept Med, Gainesville, FL 32610 USA. [Dyer, Lisa M.; Brown, Kevin D.] Univ Florida, Dept Biochem & Mol Biol, Gainesville, FL 32610 USA. [Hochwald, Steven N.] Univ Florida, Dept Surg, Gainesville, FL 32610 USA. [Yang, Sherry X.] NCI Frederick, Natl Clin Target Validat Lab, Frederick, MD USA. [Hollingshead, Melinda] NCI Frederick, Dev Therapeut Program, Frederick, MD USA. [Hunter, Kent W.] NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. [Marquez, Victor E.] NCI, Med Chem Lab, Bethesda, MD 20892 USA. [Steeg, Patricia] NCI, Mol Pharmacol Lab, Bethesda, MD 20892 USA.;Zajac-Kaye, M (reprint author), Univ Florida, Coll Med, Dept Anat & Cell Biol, Canc & Genet Res Complex,Room 360,2033 Mowry Rd, Gainesville, FL 32610 USA;mzajackaye@ufl.edu
    1. Year: 2012
    2. Date: Feb
  2. Journal: Molecular Cancer Therapeutics
    1. 11
    2. 2
    3. Pages: 370-382
  4. Type of Article: Article
  5. ISSN: 1535-7163
  1. Abstract:

    Zebularine is a novel potent inhibitor of both cytidine deaminase and DNA methylation. We examined the effect of zebularine on mammary tumor growth in genetically engineered MMTV-PyMT transgenic mice that develop mammary tumors at 60 days of age with 100% penetrance. The MMTV-PyMT transgenic mice were randomized at 46 days of age into control (n = 25) and zebularine (n = 25) treatment groups and monitored for parameters of tumor growth. Zebularine was administered at 5 mg/mL in drinking water. We observed a significant delay in the growth of mammary tumors in zebularine-treated mice with a statistically significant reduction (P = 0.0135) in total tumor burden at 94 days of age when the mice were sacrificed. After 48 days of zebularine treatment, the tumors were predominantly necrotic compared with untreated animals. In addition, a high apoptotic index by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay was observed as early as 13 days following treatment. Immunoblot analysis showed depletion of DNMT1 and partial depletion of DNMT3b after zebularine treatment. Microarray analyses of global gene expression identified upregulation of twelve methylation-regulated genes as well as a set of candidate cancer genes that participate in cell growth and apoptosis. In summary, zebularine inhibits the growth of spontaneous mammary tumors and causes early onset of tumor cell necrosis and apoptosis in a genetically engineered mouse model of breast cancer. Defining the parameters of zebularine-mediated tumor inhibition may advance the future development of DNA methyltransferase inhibitors as an effective cancer treatment. Mol Cancer Ther; 11(2); 370-82. (C) 2011 AACR.

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External Sources

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  2. DOI: 10.1158/1535-7163.mct-11-0458
  3. View record in Web of Science®
  4. WOS: 000300415300012

Library Notes

  1. Fiscal Year: FY2011-2012
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