Figure 3: Combination of HDACi with proteasome inhibitors induces cellular stress. Synergistic apoptosis is observed between HDACi and three structurally different proteasome inhibitors—marizomib, carfilzomib, and bortezomib. The cell death observed with this therapeutic strategy is generally oxidant dependent. Individually both proteasome inhibitors and HDACi generate ROS, either via mitochondrial injury or by disregulating antioxidant systems as described in the text. When paired, these two compounds dramatically increase oxidative stress, which leads to apoptosis. High levels of ROS can also cause damage to proteins which can contribute to ER stress. Inhibiting the proteasome also results in aggregates of conjugated ubiquitin proteins that were originally to be degraded by the proteolytic complex. HDAC 6 mediates aggresome formation as a cytoprotective measure in the cell. Addition of HDACi disrupts aggresomes, leading to ER stress, which can stimulate oxidative stress or directly induce apoptosis.