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Research Paper
Mitoxantrone Mediates Demethylation and Re-Expression of Cyclin D2, Estrogen Receptor 14.3.3 Sigma In Breast Cancer Cells
Belinda S. Parker, Suzanne M. Cutts, Abraham Nudelman, Ada Rephaeli, Don R. Phillips and Saraswati Sukumar
volume 2 | issue 3
may/june 2003Pages: 259-263
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In addition to its action as a topoisomerase II poison, mitoxantrone is activated by formaldehyde to bind DNA, forming DNA-adducts specifically at 5’CpG and CpA sequences, with an enhancement of adducts at methylated CpG sites. The butyric acid prodrug, AN-9 (pivaloyloxymethyl butyrate) releases formaldehyde upon cellular hydrolysis and our previous studies have shown that mitoxantrone acts synergistically with AN-9 in cytotoxicity assays. In this paper, we investigated the impact of methylation levels in the cell on mitoxantrone-induced cytotoxicity using the colon cancer cell line HCT116 and its derived DNA methyltransferase (DNMT) 1 and DNMT 3a knockout (DKO8) cell line. We found that decreased methylation levels in the DNMT-null cells led to at least a 2-fold reduction in mitoxantrone-induced cytotoxicity. Next, we studied the impact of mitoxantrone alone, and in combination with AN-9, on hypermethylated genes and their mRNA expression in breast cancer cells. Using methylation-specific PCR and RT-PCR, we found that mitoxantrone treatment of breast cancer cell lines resulted in demethylation of the 14.3.3-sigma, Cyclin D2 and ER genes, followed by re-expression of their mRNA. The effect of mitoxantrone on re-expression of key genes involved in cell cycle regulation, and ensuing death of the cells may be an additional, previously undiscovered mechanism of action of mitoxantrone.
We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:
Download PDFIf the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.