Proposed model of combination effect of an HDACI and PEITC on leukemia cells. An HDACI activates NOX and induces ROS stress, which contributes to cellular damage and cytotoxicity. As a secondary response, increase of ROS also results in translocation of Nrf2, a transcription factor, from cytosol to nucleus, leading to up-regulation of its downstream targets, including antioxidants and phase 2 detoxification genes. Among these genes, the effectiveness of GST to detoxify foreign compounds depends on GSH levels, which is determined by GCL, the key enzyme for glutathione synthesis and GSR, the enzyme responsible for glutathione regeneration. GPX relies on glutathione as a substrate to eliminate H₂O_2. As such, GSH system is critical for cellular defense against oxidative injury. Addition of PEITC, the compound capable of depleting cellular GSH, inhibits such defense system and potentiates the antileukemia activity of HDACIs.