Smac mimetics, or IAP antagonists, are a class of drugs currently being evaluated as anti-cancer therapeutics. These agents antagonize IAP proteins, including cIAP1/2 and XIAP, to induce cell death via apoptotic or, upon caspase-8 deficiency, necroptotic cell death pathways. Many cancer cells are unresponsive to Smac mimetic treatment as a single agent but can be sensitized to killing in the presence of the cytokine TNFα, provided either exogenously or via autocrine production. We found that high concentrations of a subset of Smac mimetics could provoke death in cells that did not produce TNFα, despite sensitization at lower concentrations by TNFα. The ability of these drugs to kill did not correlate with valency. These cells remained responsive to the lethal effects of Smac mimetics at high concentrations despite genetic or pharmacological impairments in apoptotic, necroptotic, pyroptotic, autophagic and ferroptotic cell death pathways. Analysis of dying cells revealed necrotic morphology, which was accompanied by the release of lactate dehydrogenase and cell membrane rupture without prior phosphatidylserine exposure implying cell lysis, which occurred over a several hours. Our study reveals that cells incapable of autocrine TNFα production are sensitive to some Smac mimetic compounds when used at high concentrations, and this exposure elicits a lytic cell death phenotype that occurs via a mechanism not requiring apoptotic caspases or necroptotic effectors RIPK3 or MLKL. These data reveal the possibility that non-canonical cell death pathways can be triggered by these drugs when applied at high concentrations.

中文翻译：

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Smac模拟物可引起既不凋亡也不坏死的溶细胞死亡。

Smac模拟物或IAP拮抗剂是目前被评估为抗癌治疗剂的一类药物。这些药剂拮抗IAP蛋白，包括cIAP1 / 2和XIAP，以通过凋亡或在caspase-8缺乏时通过坏死性细胞死亡途径诱导细胞死亡。许多癌细胞作为单一药物对Smac模拟物治疗无反应，但是可以在细胞因子TNFα的存在下被敏锐地杀死，这是由外源或通过自分泌产生的。我们发现，高浓度的Smac模拟物子集可以激起不产生TNFα的细胞死亡，尽管在较低的浓度下TNFα会致敏。这些药物的杀灭能力与化合价无关。这些细胞尽管在凋亡，坏死性，烧伤性，自噬性和受精卵性细胞死亡途径中存在遗传或药理学损害，但仍对高浓度Smac模拟物的致死作用有反应。对垂死细胞的分析显示出坏死的形态，伴随有乳酸脱氢酶的释放和细胞膜破裂，而先前的磷脂酰丝氨酸暴露没有暗示细胞裂解，而裂解发生了数小时。我们的研究表明，不能以高水平使用自分泌TNFα的细胞对某些Smac模拟化合物敏感，并且这种暴露会引起裂解性细胞死亡表型，该表型通过不需要凋亡胱天蛋白酶或坏死性因子RIPK3或MLKL的机制发生。