Bday Jaweher, Souid Moufida, Pires Vivien, Gabbouj Sallouha, Véjux Anne, Lizard Gérard, Hassen Elham
Molecular Immuno-Oncology Laboratory, University of Monastir, Monastir, Tunisia.
Higher Institute of Biotechnology of Monastir, University of Monastir, Monastir, Tunisia.
J Biochem Mol Toxicol. 2025 Feb;39(2):e70130. doi: 10.1002/jbt.70130.
Arginase plays a crucial role in the urea cycle; it also has immunosuppressive and pro-tumor effects. The present study aimed to assess the effects of arginase inhibition by thymoquinone (2-Isopropyl-5-methyl-1,4-benzoquinone), an active compound of Nigella sativa, on cell death in the MDA-MB-231 triple-negative breast tumor cell line. Cell viability assays, Western blot analysis, and flow cytometry analysis were used to characterize oxidative stress and cell death. Our results showed that inhibition of arginase activity with thymoquinone significantly increased intracellular nitric oxide levels and resulted in overproduction of cellular and mitochondrial reactive oxygen species. Reductions in cell viability, cycle arrest, and increased cell death were also observed. Loss of transmembrane mitochondrial potential, activation of caspase-3, -7, and -9, cleavage of PARP, condensation and/or fragmentation of the nuclei, suggest that this cell death involved apoptosis. Furthermore, a cytoplasm vacuole formation and an increase in the ratio of [LC3-II/LC3-I] suggests a concomitant activation of autophagy with apoptosis. Altogether, the present study highlighted that arginase inhibition with thymoquinone induces a hybrid type of cell death defined as oxiapoptophagy. Thus, arginase inhibition with thymoquinone in the MDA-MB-231 cell line could be, in part, involved in the anticancer effect of thymoquinone.
精氨酸酶在尿素循环中起关键作用；它还具有免疫抑制和促肿瘤作用。本研究旨在评估黑种草的活性化合物百里醌（2-异丙基-5-甲基-1,4-苯醌）抑制精氨酸酶对MDA-MB-231三阴性乳腺癌细胞系细胞死亡的影响。采用细胞活力测定、蛋白质免疫印迹分析和流式细胞术分析来表征氧化应激和细胞死亡。我们的结果表明，百里醌抑制精氨酸酶活性可显著提高细胞内一氧化氮水平，并导致细胞和线粒体活性氧的过量产生。还观察到细胞活力降低、细胞周期停滞和细胞死亡增加。线粒体跨膜电位丧失、半胱天冬酶-3、-7和-9激活、聚ADP核糖聚合酶裂解、细胞核凝聚和/或碎片化，表明这种细胞死亡涉及凋亡。此外，细胞质空泡形成以及[LC3-II/LC3-I]比值增加表明自噬与凋亡同时被激活。总之，本研究强调百里醌抑制精氨酸酶可诱导一种定义为氧化凋亡自噬的混合型细胞死亡。因此，在MDA-MB-231细胞系中百里醌抑制精氨酸酶可能部分参与了百里醌的抗癌作用。
