Histone Deacetylase Inhibitors Protect against and Mitigate the Lethality of Total-Body Irradiation in Mice

Department of Radiation Oncology, Henry Ford Hospital, Detroit, Michigan 48202, USA.
Radiation Research (Impact Factor: 2.91). 05/2008; 169(4):474-8. DOI: 10.1667/RR1245.1
Source: PubMed


It was hypothesized that histone deacetylase (HDAC) inhibitors may increase survival after total-body irradiation (TBI) based on previous reports demonstrating that HDAC inhibitors stimulate the proliferation of bone marrow stem cells. Using the time for mice to lose 20% or more of their weight as the end point, two HDAC inhibitors, valproic acid and trichostatin-A, were found to reduce lethality in a dose-dependent manner. HDAC inhibitors were effective at reducing lethality when given either 24 h before or 1 h after TBI. The results indicate that HDAC inhibitors have potential for protecting against and mitigating radiation-induced lethality.

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    • "Our findings will inform future clinical studies designed to explore how panobinostat might be used in combination with other therapies to improve outcomes in patients with epithelial tumours, for example, through its sequential delivery with other mitosis blocking agents such as taxanes. Given that there is now considerable interest in exploring how epigenetic priming may make cancer cells more sensitive to radiotherapy, there is a compelling case for adding panobinostat to the list of HDAC inhibitors currently under evaluation as potential modulators of radiation sensitivity414243. We are currently addressing these possibilities to optimise the use of panobinostat in future pre-clinical trials designed to determine whether these combinations would be more effective and less toxic than current regimens. "
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    ABSTRACT: It has been shown that valproic acid (VA) enhances the proliferation and self-renewal of normal hematopoietic stem cells and that breast cancer stem/progenitor cells can be resistant to radiation. From these data, we hypothesized that VA would fail to radiosensitize breast cancer stem/progenitor cells grown to three-dimensional (3D) mammospheres. We used the MCF7 breast cancer cell line grown under stem cell-promoting culture conditions (3D mammosphere) and standard nonstem cell monolayer culture conditions (two-dimensional) to examine the effect of pretreatment with VA on radiation sensitivity in clonogenic survival assays and on the expression of embryonic stem cell transcription factors. 3D-cultured MCF-7 cells expressed higher levels of Oct4, Nanog, and Sox2. The 3D passage enriched self-renewal and increased radioresistance in the 3D mammosphere formation assays. VA radiosensitized adherent cells but radioprotected 3D cells in single-fraction clonogenic assays. Moreover, fractionated radiation sensitized VA-treated adherent MCF7 cells but did not have a significant effect on VA-treated single cells grown to mammospheres. We have concluded that VA might preferentially radiosensitize differentiated cells compared with those expressing stem cell surrogates and that stem cell-promoting culture is a useful tool for in vitro evaluation of novel cancer therapeutic agents and radiosensitizers.
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