Greco Giulia, Schnekenburger Michael, Catanzaro Elena, Turrini Eleonora, Ferrini Fabio, Sestili Piero, Diederich Marc, Fimognari Carmela
Dipartimento di Scienze per la Qualità della Vita, Alma Mater Studiorum-Università di Bologna, Corso d'Augusto 237, 47921 Rimini, Italy.
Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, 9 Rue Edward Steichen, L-2540 Luxembourg, Luxembourg.
Cancers (Basel). 2021 Dec 24;14(1):76. doi: 10.3390/cancers14010076.
In recent years, natural compounds have emerged as inducers of non-canonical cell death. The isothiocyanate sulforaphane (SFN) is a well-known natural anticancer compound with remarkable pro-apoptotic activity. Its ability to promote non-apoptotic cell-death mechanisms remains poorly investigated. This work aimed to explore the capacity of SFN to induce non-apoptotic cell death modalities. SFN was tested on different acute myeloid leukemia cell lines. The mechanism of cell death was investigated using a multi-parametric approach including fluorescence microscopy, western blotting, and flow cytometry. SFN triggered different cell-death modalities in a dose-dependent manner. At 25 μM, SFN induced caspase-dependent apoptosis and at 50 μM ferroptosis was induced through depletion of glutathione (GSH), decreased GSH peroxidase 4 protein expression, and lipid peroxidation. In contrast, necroptosis was not involved in SFN-induced cell death, as demonstrated by the non-significant increase in phosphorylation of receptor-interacting protein kinase 3 and phosphorylation of the necroptotic effector mixed lineage kinase domain-like pseudokinase. Taken together, our results suggest that the antileukemic activity of SFN can be mediated via both ferroptotic and apoptotic cell death modalities.
近年来，天然化合物已成为非经典细胞死亡的诱导剂。异硫氰酸酯萝卜硫素（SFN）是一种著名的具有显著促凋亡活性的天然抗癌化合物。其促进非凋亡细胞死亡机制的能力仍研究不足。这项工作旨在探索SFN诱导非凋亡细胞死亡方式的能力。对不同的急性髓系白血病细胞系进行了SFN测试。使用包括荧光显微镜、蛋白质免疫印迹和流式细胞术在内的多参数方法研究了细胞死亡机制。SFN以剂量依赖的方式触发了不同的细胞死亡方式。在25μM时，SFN诱导了半胱天冬酶依赖性凋亡，而在50μM时，通过消耗谷胱甘肽（GSH）、降低GSH过氧化物酶4蛋白表达和脂质过氧化诱导了铁死亡。相比之下，受体相互作用蛋白激酶3的磷酸化和坏死性凋亡效应器混合谱系激酶结构域样假激酶的磷酸化没有显著增加，这表明坏死性凋亡不参与SFN诱导的细胞死亡。综上所述，我们的结果表明，SFN的抗白血病活性可通过铁死亡和凋亡细胞死亡方式介导。
