This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kim, I. A. Articles by Kao, G. D. Search for Related Content PubMed PubMed Citation Articles by Kim, I. A. Articles by Kao, G. D.

Histone Deacetylase Inhibitor–Mediated Radiosensitization of Human Cancer Cells: Class Differences and the Potential Influence of p53

Authors' Affiliations: ¹ Department of Radiation Oncology and ² Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea and ³ Department of Radiation Oncology, Philadelphia Veterans Affair Medical Center, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

Requests for reprints: Il Han Kim, Department of Radiation Oncology, Seoul National University College of Medicine, 28 Yongon-dong, Jongno-gu, Seoul 110-744, Korea. Phone: 82-2-2072-2528; Fax: 82-2-742-2073; E-mail: ihkim{at}snu.ac.kr

Histone deacetylase inhibitors (HDI) are emerging as potentially useful components of the anticancer armamentarium and as useful tools to dissect mechanistic pathways. HDIs that globally inhibit histone deacetylases (HDAC) have radiosensitizing effects, but the relative contribution of specific HDAC classes remains unclear. Newly characterized HDIs are now available that preferentially inhibit specific HDAC classes, including SK7041 (inhibits class I HDACs) and splitomicin (inhibits class III HDACs). We investigated in human cancer cells the relative radiosensitizations that result from blocking specific HDAC classes. We found that trichostatin A (TSA; inhibitor of both class I and II HDACs) was the most effective radiosensitizer, followed by the class I inhibitor SK7041, whereas splitomicin (inhibitor of class III) had least effect. Interestingly, radiosensitization by TSA in cell lines expressing p53 was more pronounced than in isogenic lines lacking p53. Radiosensitization of cells expressing p53 by TSA was reduced by pifithrin-, a small-molecule inhibitor of p53. In contrast, the radiosensitization by TSA of cells expressing low levels of p53 was enhanced by transfection of wild-type p53–expressing vector or pretreatment with leptomycin B, an inhibitor of nuclear export that increased intracellular levels of p53. These effects on radiosensitization were respectively muted or not seen in cells treated with SK7041 or splitomicin. To our knowledge, this may be among the first systematic investigations of the comparative anticancer effects of inhibiting specific classes of HDACs, with results suggesting differences in the degrees of radiosensitization, which in some cell lines may be influenced by p53 expression.

This article has been cited by other articles:

				V. Duong, C. Bret, L. Altucci, A. Mai, C. Duraffourd, J. Loubersac, P.-O. Harmand, S. Bonnet, S. Valente, T. Maudelonde, et al. Specific Activity of Class II Histone Deacetylases in Human Breast Cancer Cells Mol. Cancer Res., December 1, 2008; 6(12): 1908 - 1919. [Abstract] [Full Text] [PDF]

				P. Chinnaiyan, D. Cerna, W. E. Burgan, K. Beam, E. S. Williams, K. Camphausen, and P. J. Tofilon Postradiation Sensitization of the Histone Deacetylase Inhibitor Valproic Acid Clin. Cancer Res., September 1, 2008; 14(17): 5410 - 5415. [Abstract] [Full Text] [PDF]