Figure 4: Several therapeutic combinations with HDACi show promising results. Some agents which have been shown to cause synergistic cell death when combined with HDACi include (1) DNA-damaging agents, such as radiation and many chemotherapies, which may take advantage of the increased access to DNA, provided by the “loose” chromatin arrangement after HDACi treatment, to cause increased DNA damage, (2) modulators of methylation, such as histone demethylase inhibitors and DNA methyltransferase inhibitors, which have been shown to contribute changes to the methylome that act synergistically with the actions of HDACi, (3) proteasome inhibitors, which increase cellular stress and lead to production of reactive oxygen species, can synergize with HDACi, and (4) ROS-generating agents, such as adaphostin, work with HDACi to amplify ROS production, adding to the already increased ROS levels in cancer cells until toxic levels lead to cell death.