Smac mimetic primes apoptosis-resistant acute myeloid leukaemia cells for cytarabine-induced cell death by triggering necroptosis
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- 作者：Joerg Chromik ; Charlotta Safferthal ; Hubert Serve ; Simone Fulda
- 关键词：AML ; acute myeloid leukaemia ; AraC ; Cytarabine ; BIR ; Baculovirus IAP Repeat ; CBF ; core-binding factor ; CI ; combination index ; cIAP1 ; cellular inhibitor of apoptosis protein 1 ; FACS ; fluorescence-activated cell-sorting ; FADD ; FAS-associated death domain protein ; IAP ; Inhibitor of apoptosis ; MLKL ; mixed lineage kinase domain-like protein ; MMP ; mitochondrial membrane potential ; Nec ; Necrostatin-1 ; NF-魏B ; Nuclear Factor kappaB ; PI ; propidium iodide ; RING ; Really Interesting New Gene ; RIP1 ; Receptor
- 刊名：Cancer Letters
- 出版年：1 March, 2014
- 年：2014
- 卷：344
- 期：1
- 页码：101-109
- 全文大小：755 K
文摘
The prognosis for patients with acute myeloid leukaemia (AML) is still poor, thus calling for novel treatment strategies. Here, we report that the small-molecule Smac mimetic BV6, which antagonizes Inhibitor of Apoptosis (IAP) proteins, acts in concert with cytarabine (AraC) to trigger cell death in AML cells in a highly synergistic manner (combination index 0.02-0.27). Similarly, BV6 cooperates with AraC to trigger cell death in primary AML samples, underscoring the clinical relevance of our findings. Molecular studies reveal that the TNF伪-blocking antibody Enbrel significantly reduces BV6/AraC-induced cell death, demonstrating that an autocrine/paracrine TNF伪 loop mediates cell death. Furthermore, BV6 and AraC synergize to induce loss of mitochondrial membrane potential, caspase activation and DNA fragmentation, consistent with apoptotic cell death. Nevertheless, the caspase inhibitor zVAD.fmk fails to protect against BV6/AraC-induced cell death. Intriguingly, this cell death upon caspase inhibition is significantly reduced by pharmacological inhibition of two key components of necroptosis signaling, i.e. by RIP1 kinase inhibitor Necrostatin-1 or MLKL inhibitor NSA. Thus, BV6 sensitizes AML cells to AraC-induced cell death and overcomes apoptosis resistance by triggering necroptosis as alternative form of cell death. These findings have important implications for Smac mimetic-based strategies to bypass apoptosis resistance of AML.