Synergistic interaction of Smac mimetic and IFNα to trigger apoptosis in acute myeloid leukemia cells

Therapeutic targeting of inhibitor of apoptosis (IAP) proteins by small-molecule inhibitors such as Smac mimetic is considered as a promising anticancer strategy to elicit apoptosis. Recent advances have renewed the interest in exploiting the antileukemic activity of interferon (IFN)alpha for the treatment of acute myeloid leukemia (AML). Here, we identify a novel synergistic interaction of the Smac mimetic BV6 and IFN alpha to trigger cell death in AML cells. Calculation of combination index (CI) confirms the synergism of BV6 and IFN alpha. In contrast to AML cells, no synergistic toxicity of BV6 and IFN alpha at equimolar concentrations is found against normal peripheral blood lymphocytes. BV6 and IFN alpha act in concert to stimulate expression of tumor necrosis factor (TNF)alpha and its secretion into the supernatant, thereby initiating an autocrine/paracrine TNF alpha/TNF receptor 1 (TNFR1) loop that drives cell death by BV6 and IFN alpha. Consistently, pharmacological inhibition of TNF alpha by the TNF alpha-blocking antibody Enbrel or genetic silencing of TNFR1 significantly reduces BV6/IFN alpha-induced cell death. In addition, BV6/IFN alpha-induced cell death depends on interferon regulatory factor (IRF)1, since RNA interference-imposed knockdown of IRF1 significantly rescues cell death. In conclusion, the identification of a novel synergistic antileukemic combination of Smac mimetic and IFN alpha has important implications for the development of innovative treatment strategies in AML. (C) 2014 Elsevier Ireland Ltd. All rights reserved.