251. Inhibition of histone deacetylase activity is a novel function of the antifolate drug methotrexate.
- Author
-
Yang PM, Lin JH, Huang WY, Lin YC, Yeh SH, and Chen CC
- Subjects
- Antimetabolites, Antineoplastic chemistry, Cell Line, Tumor, Folic Acid Antagonists chemistry, Histone Deacetylase Inhibitors chemistry, Humans, Methotrexate chemistry, Antimetabolites, Antineoplastic pharmacology, Folic Acid Antagonists pharmacology, Histone Deacetylase Inhibitors pharmacology, Histone Deacetylases metabolism, Methotrexate pharmacology
- Abstract
Methotrexate (MTX) is a dihydrofolate reductase (DHFR) inhibitor widely used for treating human cancers, and overexpression of histone deacetylase (HDAC) is usually found in tumors. HDAC inhibitors (HDACi) can reactivate tumor suppressor genes and serve as potential anti-cancer drugs. In this study, we found that MTX shared structural similarity with some HDACi and molecular modeling showed that MTX indeed docks into the active site of HDLP, a bacterial homologue of HDAC. Subsequent in vitro assay demonstrated MTX's inhibition on HDAC activity in human cancer cells. The global acetylation of histone H3 was also induced by MTX. Moreover, MTX inhibited immunoprecipitated HDAC1/2 activity but not their protein levels. This study provides evidence that MTX inhibits HDAC activity., (Copyright 2009 Elsevier Inc. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF