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First published on August 31, 2004; DOI: 10.1124/mol.104.002634

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Received for publication May 12, 2004.
Revised August 11, 2004.
Accepted for publication August 27, 2004.

Doxorubicin inhibits DNMT1 resulting in conditional apoptosis

Tomoki Yokochi 1 Keith D Robertson 2*

1 National Cancer Institute / NIH 2 University of Florida

* Address correspondence to: E-mail: keithr{at}ufl.edu

Abstract

Chemotherapy utilizing DNA intercalators is one of the most successful approaches to cancer treatment. Although DNA intercalators are believed to inhibit DNA polymerases and topoisomerases resulting in the induction of apoptosis in tumor cells, other factors potentially inhibited by the anthracycline antibiotics remain to be elucidated. Here we show that the enzymatic activity of DNMT1, the primary DNA methyltransferase in mammalian cells, is inhibited by DNA intercalators such as doxorubicin in an in vitro assay. Enzymatic analyses indicate that doxorubicin inhibits the catalytic activity of DNMT1 via DNA intercalation. We also found that apoptosis was induced in DNMT1+/+ HCT116 cells by only a limited range of doxorubicin dose, meaning that apoptotic cell death is "conditional" with respect to the concentration of the DNA intercalating drug. Interestingly, conditional apoptosis is not observed in human colorectal cancer cells lacking DNMT1 but can be induced in DNMT1-/- cells by transfection of a plasmid expressing DNMT1. Our results suggest that DNMT1 is one of the major targets of doxorubicin resulting in drug-induced apoptosis in human cancer cells. We propose that expression levels of DNMT1 in tumor cells may affect the effectiveness of doxorubicin in chemotherapy.


Key words: Enzymology, Apoptosis, DNA damage and repair, Mechanisms of cell killing/apoptosis, DNA intercalation


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