Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan.
Graduate Institute of Biomedical Science, China Medical University, Taichung, Taiwan.
Environ Toxicol. 2024 Nov;39(11):5059-5073. doi: 10.1002/tox.24378. Epub 2024 Jul 26.
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 IC 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 G 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. DiOC 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 Ca 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 G arrest and apoptosis in NPC cells. Naringin-induced ROS-mediated G arrest and mitochondrial-, death receptor-, and endoplasmic reticulum stress-mediated apoptosis may be a promising strategy for treating NPC.
柚皮苷是葡萄柚或柑橘中的一种生物类黄酮化合物，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。本研究旨在探讨柚皮苷对鼻咽癌（NPC）细胞的抗癌作用。柚皮苷对 NPC-TW039 和 NPC-TW076 细胞的细胞毒性作用分别为 24 或 48 h 的 IC372/328 和 394/307 μM，而对正常牙龈上皮（SG）细胞的毒性作用较小（>500/500 μM）。我们发现，柚皮苷通过抑制 NPC 细胞中环素 D1、环素 A 和 CDK2 的表达，上调 p21 蛋白，引发 G1 期阻滞。将 NPC 细胞暴露于柚皮苷中会引发一系列导致细胞凋亡的事件，包括形态变化（细胞收缩和膜泡形成）和染色质浓缩。Annexin V 和 PI 染色表明，柚皮苷处理促进 NPC 细胞坏死和晚期凋亡。DiOC 染色显示，柚皮苷处理后线粒体膜电位下降，随后伴有细胞色素 c 释放、Apaf-1/caspase-9/-3 激活、PARP 裂解和 EndoG 在 NPC 细胞中的表达。柚皮苷上调促凋亡 Bax 蛋白表达，下调抗凋亡 Bcl-xL 蛋白表达，使 NPC 细胞中 Bax/Bcl-xL 比值失调。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，柚皮苷处理导致 Ca2+释放增加，通过增加 NPC 细胞中 IRE1、ATF-6、GRP78、GADD153 和 caspase-12 的表达引发内质网应激相关的细胞凋亡。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，可防止 NPC 细胞发生 G1 期阻滞和凋亡。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凋亡可能是治疗 NPC 的一种有前途的策略。
