Doxorubicin inhibits DNMT1, resulting in conditional apoptosis

Tomoki Yokochi, Keith D. Robertson

Research output: Contribution to journalArticle

76 Scopus citations

Abstract

Chemotherapy using 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. Herein, 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. It is noteworthy that 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.

Original languageEnglish (US)
Pages (from-to)1415-1420
Number of pages6
JournalMolecular pharmacology
Volume66
Issue number6
DOIs
StatePublished - Dec 1 2004

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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