Susceptibility and radiosensitization of human glioblastoma cells to trichostatin A, a histone deacetylase inhibitor

Purpose: Histone deacetylase inhibitors (HDAC-Is) show in vitro and in vivo antitumor activity in various types of cancer cells and are being studied in clinical trials. However, studies addressing the combination of HDAC-I and radiation are lacking. The purpose of this study was to assess the effect of trichostatin A (TSA), an HDAC-I, on the radiosensitivity of U373MG and U87MG (human glioblastoma) cell lines. Methods and Materials: Intrinsic TSA toxicity was determined by measuring survival in exponentially growing cells treated with 0-200 nM TSA for 0-24 h. To assay the radiosensitizing effect of TSA, cells were exposed to 0-200 nM TSA for 18 h before irradiation, and radiation survival curves were obtained. Radiation survival of TSA-treated cells was determined by clonogenic assay. Results: The human glioblastoma cells showed a dose-dependent reduction in survival and radiosensitization with TSA treatment in the range of 50-200 nM. Exposure to 200 nM TSA. resulted in reduced survival of both cell lines, and survival was further reduced with time. Exposure of these cells to TSA before irradiation led to dose-dependent radiosensitization. Conclusions: These results suggest that HDAC-Is may be a useful adjunct in the treatment of glioblastoma and merit further investigation. Given the limited efficacy of standard treatments for patients afflicted with glioblastoma, the results reported here provide support for clinical trials integrating HDAC-I with radiation therapy. (C) 2004 Elsevier Inc.