The pharmacological NFκB inhibitors BAY117082 and MG132 induce cell arrest and apoptosis in leukemia cells through ROS-mitochondria pathway activation

A growing body of evidence suggests the inhibition of NF kappa B as a strategy to induce cell death in tumor cells. In this work, we evaluated the effects of the pharmacological NF kappa B inhibitors BAY117082 and MG132 on leukemia cells apoptosis. BAY117082 and MG132 presented potent apoptotic effects compared to inhibitors of MAPKs, EGFR, PI3K/Akt, PKC and PKA signaling pathways. Non-tumor peripheral blood cells were insensitive to BAY117082 and MG132 apoptotic effects. BAY117082 and MG132-induced apoptosis was dependent on their ability to increase ROS as a prelude to mitochondria membrane potential (MIMP) depolarization, permeability transition pore opening and cytochrome c release. Antioxidants blocked MG132 and BAYI 17082 effects on ROS, MMP and cell death. Although apoptotic markers as phosphatidylserine externalization, chromatin condensation and sub-G1 were detected in BAY117082-treated cells, caspases activation did not occur and apoptosis was insensitive to caspase inhibitors, suggesting a caspase-independent mechanism. In contrast, MG132 induced classical apoptosis through ROS-mitochondria and subsequent caspase-9/caspase-3 activation. At sub-apoptotic concentrations, BAYI 17082 and MG132 arrested cells in G2/M phase of the cell cycle and blocked doxorubicin-induced NF kappa B, which sensitized doxorubicin-resistant cells. Data suggest that the NF kappa B inhibitors MG132 and BAY117082 are potential anti-leukemia agents. (C) 2009 Elsevier Ireland Ltd. All rights reserved.