Role of thioredoxin in the response of normal and transformed cells to histone deacetylase inhibitors Journal Article
| Authors: | Ungerstedt, J. S.; Sowa, Y.; Xu, W. S.; Shao, Y.; Dokmanovic, M.; Perez, G.; Ngo, L.; Holmgren, A.; Jiang, X.; Marks, P. A. |
| Article Title: | Role of thioredoxin in the response of normal and transformed cells to histone deacetylase inhibitors |
| Abstract: | This study examines the basis of resistance and sensitivity of normal and transformed cells to histone deacetylase inhibitor (HDACi)-induced cell death, specifically the role of caspases and thioredoxin (Trx). An important attribute of HDACis is that they induce cancer cell death at concentrations to which normal cells are relatively resistant, making them well suited for cancer therapy. The mechanism underlying this selectivity has not been understood. In this study we found that the HDACi suberoylanilide hydroxamic acid (SAHA) and MS-275, a benzamide, cause an accumulation of reactive oxygen species (ROS) and caspase activation in transformed but not normal cells. Inhibition of caspases does not block HDACi-induced cell death. These studies provide a possible mechanism that can explain why normal but not certain transformed cells are resistant to HDACi-induced cell death. The HDACi causes an increase in the level of Trx, a major reducing protein for many targets, in normal cells but not in transformed cells. The SAHA-induced increase in Trx activity in normal cells is associated with no increase in ROS accumulation. Transfection of transformed cells with Trx small interfering RNA caused a marked decrease in the level of Trx protein with an increase in ROS, a decrease in cell proliferation, and an increase in sensitivity to SAHA-induced cell death. Thus, Trx, independent of the caspase apoptotic pathway, is an important determinant of resistance of cells to HDACi-induced cell death. |
| Keywords: | controlled study; human cell; histone deacetylase inhibitor; pyridines; antineoplastic agent; neoplasms; cell proliferation; cell viability; cell cycle; apoptosis; multiple myeloma; cell growth; small interfering rna; rna, small interfering; antineoplastic activity; cancer cell culture; drug resistance, neoplasm; enzyme activity; caspase; caspase inhibitor; caspases; dimethyl sulfoxide; enzyme inhibitors; cell transformation; histone h3; vorinostat; hydroxamic acids; fibroblast; reactive oxygen species; reactive oxygen metabolite; cell line, transformed; stress; histone deacetylases; oxidation reduction reaction; n (2 aminophenyl) 4 (3 pyridinylmethoxycarbonylaminomethyl)benzamide; acetylation; histone h4; benzamide derivative; benzamides; cyclin dependent kinase inhibitor 1; thioredoxin; ms-275; suberoylanilde hydroxamic acid |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 102 |
| Issue: | 3 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2005-01-18 |
| Start Page: | 673 |
| End Page: | 678 |
| Language: | English |
| DOI: | 10.1073/pnas.0408732102 |
| PUBMED: | 15637150 |
| PROVIDER: | scopus |
| PMCID: | PMC543461 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 249" - "Export Date: 24 October 2012" - "CODEN: PNASA" - "Source: Scopus" |
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