Histone deacetylase inhibitor enhances 5-fluorouracil cytotoxicity by down-regulating thymidylate synthase in human cancer cells
Open Access
- 1 December 2006
- journal article
- Published by American Association for Cancer Research (AACR) in Molecular Cancer Therapeutics
- Vol. 5 (12), 3085-3095
- https://doi.org/10.1158/1535-7163.mct-06-0419
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]Keywords
This publication has 39 references indexed in Scilit:
- Phase I Study of an Oral Histone Deacetylase Inhibitor, Suberoylanilide Hydroxamic Acid, in Patients With Advanced CancerJournal of Clinical Oncology, 2005
- Phase I and Pharmacokinetic Study of MS-275, a Histone Deacetylase Inhibitor, in Patients With Advanced and Refractory Solid Tumors or LymphomaJournal of Clinical Oncology, 2005
- Biology of SNU Cell LinesCancer Research and Treatment, 2005
- A phase 1 and pharmacodynamic study of depsipeptide (FK228) in chronic lymphocytic leukemia and acute myeloid leukemiaBlood, 2004
- Phase II trial of the histone deacetylase inhibitor pivaloyloxymethyl butyrate (Pivanex, AN-9) in advanced non-small cell lung cancerLung Cancer, 2004
- The Missing Linker: An Unexpected Role for a Histone DeacetylaseMolecular Cell, 2003
- A “combination oligonucleotide” antisense strategy to downregulate thymidylate synthase and decrease tumor cell growth and drug resistanceCancer Gene Therapy, 2003
- New prognostic indicator for non‐small‐cell lung cancer, quantitation of thymidylate synthase by real‐time reverse transcription polymerase chain reactionInternational Journal of Cancer, 2003
- Histone-deacetylase inhibitors: novel drugs for the treatment of cancerNature Reviews Drug Discovery, 2002
- New targets for pyrimidine antimetabolites in the treatment of solid tumoursPharmacy World & Science, 1994