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  • 1
    Abstract: Smac mimetics antagonize IAP proteins, which are highly expressed in several cancers. Recent reports indicate that Smac mimetics trigger a broad cytokine response and synergize with immune modulators to induce cell death. Here, we identify a differential requirement of TRAIL or TNFalpha as mediators of IFNalpha/Smac mimetic-induced cell death depending on the cellular context. Subtoxic concentrations of Smac mimetics cooperate with IFNalpha to induce cell death in various solid tumor cell lines in a highly synergistic manner as determined by combination index. Mechanistic studies show that IFNalpha/BV6 cotreatment promotes the formation of a caspase-8-activating complex together with the adaptor protein FADD and RIP1. Assembly of this RIP1/FADD/caspase-8 complex represents a critical event, since RIP1 silencing inhibits IFNalpha/BV6-induced cell death. Strikingly, pharmacological inhibition of paracrine/autocrine TNFalpha signaling by the TNFalpha scavenger Enbrel rescues HT-29 colon carcinoma cells, but not A172 glioblastoma cells from IFNalpha/BV6-induced cell death. By comparison, A172 cells are significantly protected against IFNalpha/BV6 treatment by blockage of TRAIL signaling through genetic silencing of TRAIL or its cognate receptor TRAIL receptor 2 (DR5). Despite this differential requirement of TNFalpha and TRAIL signaling, mRNA and protein expression is increased by IFNalpha/BV6 cotreatment in both cell lines. Interestingly, A172 cells turn out to be resistant to exogenously added recombinant TNFalpha even in the presence of BV6, whereas they display a high sensitivity towards TRAIL/BV6. In contrast, BV6 efficiently sensitizes HT-29 cells to TNFalpha while TRAIL only had limited efficacy. This demonstrates that a differential sensitivity towards TRAIL or TNFalpha determines the dependency on either death receptor ligand for IFNalpha/Smac mimetic-induced cell death. Thus, by concomitant stimulation of both death receptor systems IFNalpha/Smac mimetic combination treatment is an effective strategy to induce cell death in TNFalpha- or TRAIL-responsive cancers.
    Type of Publication: Journal article published
    PubMed ID: 26788912
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  • 2
    Abstract: The prognosis of metastatic or relapsed renal cell carcinoma (RCC) is still very poor, highlighting the need for new treatment strategies. Here, we identify a cooperative antitumor activity of interferon-alpha (IFNalpha) together with the Smac mimetic BV6 that antagonizes antiapoptotic IAP proteins. BV6 and IFNalpha act together to reduce cell viability and to induce apoptosis in various RCC cell lines. Molecular studies revealed that BV6/IFNalpha co-treatment triggers apoptosis independently of autocrine/paracrine Tumor Necrosis Factor (TNF)alpha signaling, since the TNFalpha-blocking antibody Enbrel fails to rescue cell death. Importantly, knockdown of Receptor-Interacting Protein (RIP)1 significantly decreases BV6/IFNalpha-mediated apoptosis, whereas the RIP1 kinase inhibitor necrostatin-1 (Nec-1) provides no protection. This demonstrates that RIP1 protein is critically required for BV6/IFNalpha-induced apoptosis, while RIP1 kinase activity is dispensable, pointing to a scaffold function of RIP1. Consistently, BV6 and IFNalpha cooperate to trigger the interaction of RIP1, Fas-Associated Death Domain protein (FADD) and caspase-8 to form a cytosolic cell death complex that drives caspase activation. Addition of the broad-range caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD.fmk) significantly protects RCC cells against BV6/IFNalpha-induced apoptosis, demonstrating that caspase activity is required for apoptosis. In conclusion, the combination approach of IFNalpha and BV6 represents a promising strategy for cooperative induction of apoptosis in RCC cells, which warrants further investigation.
    Type of Publication: Journal article published
    PubMed ID: 26912071
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  • 3
    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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  • 4
    Abstract: Since cancer cells often evade apoptosis, induction of necroptosis as another mode of programmed cell death is considered a promising therapeutic alternative. Here, we identify a novel synergistic interaction of Smac mimetics that antagonize x-linked Inhibitor of Apoptosis (XIAP), cellular Inhibitor of Apoptosis (cIAP) 1 and 2 with interferon (IFN)gamma to induce necroptosis in apoptosis-resistant cancer cells in which caspase activation is blocked. This synergism is confirmed by calculation of combination indices (CIs) and found in both solid and hematological cancer cell lines as well as for different Smac mimetics (i.e. BV6, Birinapant), pointing to a broader relevance. Importantly, individual genetic knockdown of key components of necroptosis signaling, i.e. receptor-interacting protein (RIP) 1, RIP3 or mixed lineage kinase domain-like pseudokinase (MLKL), significantly protects from BV6/IFNgamma-induced cell death. Similarly, pharmacological inhibitors of RIP1 (necrostatin-1(Nec-1)), RIP3 (GSK'872) or MLKL (necrosulfonamide (NSA)) significantly reduce BV6/IFNgamma-stimulated cell death. Of note, IFN-regulatory factor (IRF)1 is required for BV6/IFNgamma-mediated necroptosis, as IRF1 silencing provides protection from cell death. By comparison, antibodies blocking tumor necrosis factor (TNF)alpha, TNF-related apoptosis-inducing ligand (TRAIL) or CD95 ligand fail to inhibit BV6/IFNgamma-induced cell death, pointing to a mechanism independently of death receptor ligands. This is the first report showing that Smac mimetics synergize with IFNgamma to trigger necroptosis in apoptosis-resistant cancer cells with important implications for Smac mimetic-based strategies for the treatment of cancer.
    Type of Publication: Journal article published
    PubMed ID: 28923396
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