Naringin, a bioflavonoid compound from grapefruit or citrus, exerts anticancer activities on cervical, thyroid, colon, brain, liver, lung, thyroid, and breast cancers. The present investigation addressed exploring the anticancer effects of naringin on nasopharyngeal carcinoma (NPC) cells. Naringin exhibits a cytotoxic effect on NPC‐TW 039 and NPC‐TW 076 cells with IC50 372/328 and 394/307 μM for 24 or 48 h, respectively, while causing little toxicity toward normal gingival epithelial (SG) cells (>500/500 μM). We established that naringin triggered G1 arrest is achieved by suppressing cyclin D1, cyclin A, and CDK2, and upregulating p21 protein in NPC cells. Exposure of NPC cells to naringin caused a series of events leading to apoptosis including morphology change (cell shrinkage and membrane blebbing) and chromatin condensation. Annexin V and PI staining indicated that naringin treatment promotes necrosis and late apoptosis in NPC cells. DiOC6 staining showed a decline in the mitochondrial membrane potential by naringin treatment, which was followed with cytochrome c release, Apaf‐1/caspase‐9/‐3 activation, PARP cleavage, and EndoG expression in NPC cells. Naringin upregulated proapoptotic Bax and decreased antiapoptotic Bcl‐xL expression, and dysregulated Bax/Bcl‐xL ratio in NPC cells. Notably, naringin enhanced death receptor‐related t‐Bid expression. Furthermore, an increased Ca2+ release by naringin treatment which instigated endoplasmic reticulum stress‐associated apoptosis through increased IRE1, ATF‐6, GRP78, GADD153, and caspase‐12 expression in NPC cells. In addition, naringin triggers ROS production, and inhibition of naringin‐induced ROS generation by antioxidant N‐acetylcysteine resulted in the prevention of G1 arrest and apoptosis in NPC cells. Naringin‐induced ROS‐mediated G1 arrest and mitochondrial‐, death receptor‐, and endoplasmic reticulum stress–mediated apoptosis may be a promising strategy for treating NPC.

中文翻译：

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柚皮苷诱导鼻咽癌细胞中 ROS 刺激的 G1 细胞周期停滞和凋亡


柚皮苷是一种来自葡萄柚或柑橘的生物类黄酮化合物，对宫颈癌、甲状腺癌、结肠癌、脑癌、肝癌、肺癌、甲状腺癌和乳腺癌具有抗癌活性。目前的调查旨在探索柚皮苷对鼻咽癌 （NPC） 细胞的抗癌作用。柚皮苷对 NPC-TW 039 和 NPC-TW 076 细胞具有细胞毒作用，IC50 分别为 372/328 和 394/307 μM，持续 24 或 48 小时，同时对正常牙龈上皮 （SG） 细胞 （>500/500 μM） 几乎没有毒性。我们确定柚皮苷触发 G1 期阻滞是通过抑制细胞周期蛋白 D1 、 细胞周期蛋白 A 和 CDK2 以及上调 NPC 细胞中的 p21 蛋白来实现的。NPC 细胞暴露于柚皮苷会导致一系列导致细胞凋亡的事件，包括形态变化（细胞收缩和膜起泡）和染色质凝结。Annexin V 和 PI 染色表明，柚皮苷处理促进 NPC 细胞坏死和晚期细胞凋亡。DiOC6 染色显示柚皮苷处理后线粒体膜电位下降，随后在 NPC 细胞中细胞色素 c 释放、Apaf-1/caspase-9/-3 激活、PARP 切割和 EndoG 表达。在 NPC 细胞中，柚皮苷上调促凋亡 Bax 并降低抗凋亡 Bcl-xL 表达，以及 Bax/Bcl-xL 比率失调。值得注意的是，柚皮苷增强了死亡受体相关的 t-Bid 表达。此外，柚皮苷处理增加 Ca2 + 释放，通过增加 NPC 细胞中 IRE1、ATF-6、GRP78、GADD153 和 caspase-12 的表达来刺激内质网应激相关细胞凋亡。此外，柚皮苷触发 ROS 产生，抗氧化剂 N-乙酰半胱氨酸抑制柚皮苷诱导的 ROS 生成，从而防止 NPC 细胞 G1 期阻滞和细胞凋亡。 柚皮苷诱导的 ROS 介导的 G1 期阻滞和线粒体、死亡受体和内质网应激介导的细胞凋亡可能是治疗 NPC 的一种有前途的策略。