Department of Preventive Medicine, College of Korean Medicine, Kyung Hee University, Seoul 130-701, Korea.
Int J Mol Sci. 2021 Nov 12;22(22):12264. doi: 10.3390/ijms222212264.
Many anti-cancer drugs, including paclitaxel and etoposide, have originated and been developed from natural products, and traditional herbal medicines have fewer adverse effects and lesser toxicity than anti-tumor reagents. Therefore, we developed a novel complex herbal medicine, JI017, which mediates endoplasmic reticulum (ER) stress and apoptosis through the Nox4-PERK-CHOP signaling pathway in ovarian cancer cells. JI017 treatment increases the expression of GRP78, ATF4, and CHOP and the phosphorylation of PERK and eIF2α via the upregulation of Nox4. Furthermore, it increases the release of intracellular reactive oxygen species (ROS), the production of intracellular Ca, and the activation of exosomal GRP78 and cell lysate GRP78. Combination treatment using the sarco/endoplasmic reticulum Ca-ATPase inhibitor thapsigargin (TG) and JI017 reportedly induces increased ER stress and cell death in comparison to the control; however, knockdown experiments of PERK and CHOP indicated suppressed apoptosis and ER stress in JI017-treated ovarian cancer cells. Furthermore, targeting Nox4 using specific siRNA and pharmacological ROS inhibitors, including N-acetylcystein and diphenylene iodonium, blocked apoptosis and ER stress in JI017-treated ovarian cancer cells. In the radioresistant ovarian cancer model, when compared to JI017 alone, JI017 co-treatment with radiation induced greater cell death and resulted in overcoming radioresistance by inhibiting epithelial-mesenchymal-transition-related phenomena such as the reduction of E-cadherin and the increase of N-cadherin, vimentin, Slug, and Snail. These findings suggest that JI017 is a powerful anti-cancer drug for ovarian cancer treatment and that its combination treatment with radiation may be a novel therapeutic strategy for radioresistant ovarian cancer.
许多抗癌药物，包括紫杉醇和依托泊苷，都源自天然产物，并得到了发展，而且与抗肿瘤试剂相比，传统草药的副作用更小，毒性更小。因此，我们开发了一种新型的复方草药 JI017，它通过 Nox4-PERK-CHOP 信号通路在卵巢癌细胞中介导内质网（ER）应激和细胞凋亡。JI017 处理通过上调 Nox4 增加 GRP78、ATF4 和 CHOP 的表达以及 PERK 和 eIF2α 的磷酸化。此外，它增加了细胞内活性氧（ROS）的释放、细胞内 Ca 的产生以及外泌体 GRP78 和细胞裂解物 GRP78 的激活。据报道，与对照组相比，使用肌浆/内质网 Ca-ATP 酶抑制剂 thapsigargin (TG) 和 JI017 的联合处理会导致 ER 应激和细胞死亡增加；然而，PERK 和 CHOP 的敲低实验表明，JI017 处理的卵巢癌细胞中的凋亡和 ER 应激受到抑制。此外，使用特异性 siRNA 和药理学 ROS 抑制剂（包括 N-乙酰半胱氨酸和二苯基碘鎓）靶向 Nox4，可阻断 JI017 处理的卵巢癌细胞中的凋亡和 ER 应激。在耐辐射卵巢癌模型中，与单独使用 JI017 相比，JI017 与辐射联合治疗导致更大的细胞死亡，并通过抑制上皮-间充质转化相关现象（如 E-钙粘蛋白减少和 N-钙粘蛋白、波形蛋白、Slug 和 Snail 增加）来克服辐射抗性。这些发现表明 JI017 是一种强大的卵巢癌治疗抗癌药物，其与辐射的联合治疗可能是一种治疗耐辐射卵巢癌的新治疗策略。
