Radiosensitization by the Histone Deacetylase Inhibitor PCI-24781

Abstract

Purpose: PCI-24781is a novel broad spectrum histone deacetylase inhibitor that is currently in phase I clinical trials. The ability of PCI-24781to act as a radiation sensitizer and the mechanisms of radiosensitization were examined. Experimental Design: Exponentially growing human SiHa cervical and WiDr colon carcinoma cells were exposed to 0.1to 10 Amol/L PCI-24781in vitro for 2 to 20 h before irradiation and 0 to 4 h after irradiation. Single cells and sorted populations were analyzed for histone acetylation, H2AX phosphorylation, cell cycle distribution, apoptotic fraction, and clonogenic survival. Results: PCI-24781treatment for 4 h increased histone H3 acetylation and produced a modest increase in gH2AX but negligible cell killing or radiosensitization.Treatment for 24 h resulted in up to 80% cell kill and depletion of cells in S phase. Toxicity reached maximum levels at a drug concentration of f1 Amol/L, and cells in G 1 phase at the end of treatment were preferentially spared. A similar dose-modifying factor (DMF 0.1 = 1.5) was observed for SiHa cells exposed for 24 h at 0.1 to 3 Amol/L, and more radioresistant WiDr cells showed less sensitization (DMF 0.1 = 1.2). Limited radiosensitization and less killing were observed in noncycling human fibroblasts. Cell sorting experiments confirmed that depletion of S-phase cells was not a major mechanism of radiosensitization and that inner noncycling cells of SiHa spheroids could be sensitized by nontoxic doses. PCI-24781 pretreatment increased the fraction of cells with gH2AX foci 24 h after irradation but did not affect the initial rate of loss of radiation-induced gH2AX or the rate of rejoining of DNA double-strand breaks.Conclusions: PCI-24781 shows promise as a radiosensitizing agent that may compromise the accuracy of repair of radiation damage.

Breast cancer stem-like cells show dominant homologous recombination due to a larger S-G2fraction

“…31 Radiosensitization by PCI24781 has been reported for different cell lines but at much higher concentration than this study. 32 Most importantly, PCI24781 has been shown to decrease RAD51 expression and to inhibit HR, 14 and this is confirmed in the presented data ( Fig. 2A-C).…”

Combining PCI-24781, a Novel Histone Deacetylase Inhibitor, with Chemotherapy for the Treatment of Soft Tissue Sarcoma

“…In addition to monotherapy efficacy, some HDACi (including PCI-24781) have synergy with conventional chemotherapy and radiation (19)(20)(21). Consequently, we examined STS cell growth effects of PCI-24781 alone or combined with chemotherapy.…”

“…These findings suggest that PCI-24781 is potentially a STS chemosensitizer. HDACi, including PCI-24781, can synergize with DNA-damaging agents (21,22). One potential mechanism underlying such observations is that PCI-24781 can induce blockade of DNA double-strand break homologous recombination repair, at least in part due to down-regulation of Rad51 (23).…”

Scriptaid, a novel histone deacetylase inhibitor, enhances the response of human tumor cells to radiation

“…The HDAC inhibitors have shown synergistic cell killing for human tumor cell lines with chemotherapeutic drugs (23,24). In addition, several HDAC inhibitors have been reported to enhance cell killing by ionizing radiation in human tumor cells (8,(12)(13)(14)16). In this study, we demonstrated that the HDAC inhibitor scriptaid also sensitized human tumor cells to radiation.…”