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Research Articles: Therapeutics, Targets, and Development

Histone deacetylase inhibitor enhances 5-fluorouracil cytotoxicity by down-regulating thymidylate synthase in human cancer cells

¹ National Research Laboratory for Cancer Epigenetics, Cancer Research Institute; Departments of ² Tumor Biology and ³ Internal Medicine, Seoul National University College of Medicine, Seoul, Korea; and ⁴ Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea

Requests for reprints: Tae-You Kim, Division of Hematology/Medical Oncology, Department of Internal Medicine, Seoul National University College of Medicine, 28 Yongon-Dong, Chongno-Gu, Seoul 110-744, Korea. Phone: 82-2-2072-3943; Fax: 82-2-762-9662. E-mail: kimty{at}snu.ac.kr

Abstract

Thymidylate synthase (TS) overexpression is a key determinant of 5-fluorouracil (5-FU) resistance in human cancer cells. TS is also acutely up-regulated with 5-FU treatment, and, thus, novel strategies targeting TS down-regulation seem to be promising in terms of modulating 5-FU resistance. Here, we report that histone deacetylase inhibitors can reverse 5-FU resistance by down-regulating TS. By using cDNA microarrays and validation experiments, we found that trichostatin A reduced the expression of both TS mRNA and TS protein. Cotreatment with trichostatin A and cycloheximide restored TS mRNA expression, suggesting that TS mRNA is repressed through new protein synthesis. On the other hand, TS protein expression was significantly reduced by lower doses of trichostatin A (50 nmol/L). Mechanistically, TS protein was found to interact with heat shock protein (Hsp) complex, and trichostatin A treatment induced chaperonic Hsp90 acetylation and subsequently enhanced Hsp70 binding to TS, which led to the proteasomal degradation of TS protein. Of note, combined treatment with low-dose trichostatin A and 5-FU enhanced 5-FU–mediated cytotoxicity in 5-FU–resistant cancer cells in accordance with TS protein down-regulation. We conclude that a combinatorial approach using histone deacetylase inhibitors may be useful at overcoming 5-FU resistance. [Mol Cancer Ther 2006;5(12):3085–95]

Grant support: Korean Ministry of Science and Technology through the National Research Laboratory Program for Cancer Epigenetics, and by the 2002 BK 21 Project for Medicine, Dentistry and Pharmacy.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: Presented in part at the annual meeting of AACR, Anaheim, California (2005).

Received 7/18/06; revised 9/16/06; accepted 10/20/06.