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First published on August 25, 2006; DOI: 10.1124/mol.106.025866

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Received for publication April 27, 2006.
Revised August 25, 2006.
Accepted for publication August 25, 2006.

A new mechanism of methotrexate action revealed by target screening with affinity beads

Hitoshi Uga 1, Chikanori Kuramori 2, Akiko Ohta 1, Yasunori Tsuboi 1, Hiroshi Tanaka 3, Mamoru Hatakeyama 2, Yuki Yamaguchi 2, Takashi Takahashi 3, Masahiro Kizaki 4, Hiroshi Handa 2*

1 Aphoenix Inc. 2 Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology 3 Graduate School of Science and Engineering, Department of Applied Chemistry, Tokyo Institute of Tech 4 Division of Hematology, Keio University School of Medicine

* Address correspondence to: E-mail: hhanda{at}bio.titech.ac.jp

Abstract

Methotrexate (MTX) is the anti-cancer and anti-rheumatoid drug that is thought to block nucleotide synthesis and cell cycle by inhibiting dihydrofolate reductase (DHFR) activity. Recently, we developed novel affinity matrices, termed SG beads, that are easy to manipulate and compatible with surface functionalization. Using the matrices, here we present evidence that deoxycytidine kinase (dCK), an enzyme that acts in the salvage pathway of nucleotide biosynthesis, is another target of MTX. MTX modulates dCK activity differentially depending on substrate concentrations. 1-{beta}-D-arabinofuranosylcytosine (ara-C), a chemotherapy agent often used in combination with MTX, is a nucleoside analog whose incorporation into chromosome requires prior phosphorylation by dCK. Remarkably, we show that MTX enhances incorporation and cytotoxicity of ara-C through regulation of dCK activity in Burkitt's lymphoma cells. Thus, this study provides new insight into the mechanisms underlying MTX actions and also demonstrates the usefulness of the SG beads.


Key words: Structure/function/mechanism, Mechanisms of cell killing/apoptosis, Nucleoside/Nucleotide derivatives, Pharmacokinetics, metabolism and activation


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A New Mechanism of 6-((2-(Dimethylamino)ethyl)amino)-3-hydroxy-7H-indeno(2,1-c)quinolin-7-one Dihydrochloride (TAS-103) Action Discovered by Target Screening with Drug-Immobilized Affinity Beads
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[Abstract] [Full Text] [PDF]


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