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    Abstract: 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 IFNalpha to trigger cell death in AML cells. Calculation of combination index (CI) confirms the synergism of BV6 and IFNalpha. In contrast to AML cells, no synergistic toxicity of BV6 and IFNalpha at equimolar concentrations is found against normal peripheral blood lymphocytes. BV6 and IFNalpha act in concert to stimulate expression of tumor necrosis factor (TNF)alpha and its secretion into the supernatant, thereby initiating an autocrine/paracrine TNFalpha/TNF receptor 1 (TNFR1) loop that drives cell death by BV6 and IFNalpha. Consistently, pharmacological inhibition of TNFalpha by the TNFalpha-blocking antibody Enbrel or genetic silencing of TNFR1 significantly reduces BV6/IFNalpha-induced cell death. In addition, BV6/IFNalpha-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 IFNalpha has important implications for the development of innovative treatment strategies in AML.
    Type of Publication: Journal article published
    PubMed ID: 25179908
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