Overview of the Classical Histone Deacetylase Enzymes and Histone Deacetylase Inhibitors
Figure 3
Molecular pathways accounting for the additive and/or synergistic effects of combinations of HDAC inhibitors with chemotherapeutics or radiation. (a) Simplified schematic representation. Additive and/or synergistic cytotoxic effects with the use of combinations of HDAC inhibitors and chemotherapeutics may be the result of histone-acetylation-mediated changes in chromatin conformation per se (particularly in the cases where combinations with DNA targeting drugs such as anthracyclines, which require accessibility to DNA, are used). Similarly, HDAC inhibitors may enhance the cytotoxic effects of ionizing and ultraviolet (UV) radiation by increasing the accessibility of DNA to damage. A further mechanism involves HDACi-mediated regulation of gene transcription—in particular decreased expression of genes for Ku70, Ku86, DNA-PKcs, and Rad51 which are key components of double-strand break repair pathways. Paradoxically, HDAC inhibitors have been shown to protect from the effects of ionizing radiation in vivo by decreasing the expression of inflammatory cytokines such as tumor necrosis factor, TNF-α, and fibrogenic growth factors such as TGF-β1 and TGF-β2. (b) Trichostatin A (TSA) augments DNA damage induced by DNA-targeted phototherapeutics (UVASens), ionizing radiation, and chemotherapeutic agents. In the example shown, DNA double-strand break formation was as assessed by staining for γH2AX foci. Cells were treated with 1 μM TSA for 24 hours prior to one-hour incubation with 0.1 μM UVASens. Cells were then irradiated with 10 J/m2 UVA and incubated for a further one hour before staining for γH2AX. Appropriate 10 J/m2 and UVASens only controls are also depicted. In separate experiments, cells were treated with 1 μM TSA for 24 hours prior to irradiation with 2 Gy (137Cs). Cells were stained for γH2AX foci one hour after irradiation. In other experiments, cells were treated with 1 μM TSA for 24 hours prior to one-hour incubation with 1 μM doxorubicin. Cells were washed and incubated for a further 24 hours prior to staining for γH2AX.
