黄芩(Scutellaria barbata D.Don)和白花蛇舌草(Hedyotis diffusa Willd)与顺铂配伍,通过 NRF2-FTH1 自噬降解途径调节氧化应激,从而协同抑制卵巢癌的进展。

IF 3.8 3区 医学 Q1 REPRODUCTIVE BIOLOGY
Xue Sui, Bingqing Gao, Liu Zhang, Yanmin Wang, Junnan Ma, Xingchen Wu, Chenyu Zhou, Min Liu, Lin Zhang
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引用次数: 0

摘要

背景:顺铂(DDP)是最有效的抗癌药物之一,常用于晚期卵巢癌(OC)的治疗。然而,DDP具有铂类药物的明显局限性,包括化学耐药性和大剂量毒副作用。中药通常以方剂的形式呈现,以中药对为基本单位。黄芩和白花蛇舌草(SB-HD)是著名的中药对,已被证明有助于治疗多种类型的癌症。然而,SB-HD与DDP联合使用增强OC患者DDP化学敏感性的协同作用及机制尚不清楚。结果:在体外,我们发现SB-HD抑制OC细胞增殖的最佳比例为2:1,SB-HD和DDP协同降低OC细胞活力,抑制集落形成,促进细胞周期阻滞和凋亡,抑制细胞迁移和侵袭。在体内,联合治疗可显著抑制BALB/c裸鼠皮下肿瘤的生长,降低DDP的毒副作用。在机制上,SB-HD和DDP联合处理可显著促进小鼠OC细胞和肿瘤组织的氧化应激反应,降低MMP,抑制ATP的产生,降低ROS水平,提高SOD活性,提高NRF2、HO-1、ATG5和LC3的表达,降低p62和FTH1的表达。抑制剂3-MA(甲基ladenine,自噬抑制剂)和fe -1 (Ferrostatin-1,铁离子抑制剂)能有效逆转关键靶蛋白的表达变化,而ZnPP (Zinc protoporphyrin, HO-1抑制剂)则不能。通过生物信息学分析,发现NRF2和FTH1 mRNA的异常表达水平具有较高的预后价值,同时,另外四个分别与NRF2和FTH1相互作用的关键蛋白在OC的发生发展中也发挥着重要作用。结论:我们的研究结果揭示了SB-HD与DDP通过NRF2-FTH1自噬降解途径调节氧化应激对OC的协同作用,这可能为SB-HD的应用提供了重要的理论基础,并为提高DDP的化学敏感性和减少毒副作用提供了新的策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Scutellaria barbata D.Don and Hedyotis diffusa Willd herb pair combined with cisplatin synergistically inhibits ovarian cancer progression through modulating oxidative stress via NRF2-FTH1 autophagic degradation pathway.

Background: Cisplatin (DDP) is one of the most effective anticancer drugs, commonly used to treat advanced ovarian cancer (OC). However, DDP has significant limitations of platinum-based drugs, including chemical resistance and high-dose toxic side effects. Traditional Chinese medicines (TCMs) often presented in the form of formula, in which the herb pair was the basic unit. Scutellaria barbata D.Don and Hedyotis diffusa Willd (SB-HD) are famous TCMs herb pair that have been shown to help treat multiple types of cancers. However, the synergistic effects and mechanism of combination of SB-HD and DDP to enhance DDP chemosensitivity in OC are still unknown.

Results: In vitro, we found that the optimal proportion of SB-HD to inhibit the proliferation of OC cells was 2:1, SB-HD and DDP were shown to synergistically reduce the viability of OC cells, inhibit the colony formation, promote cell cycle arrest and apoptosis, as well as inhibit cell migration and invasion. In vivo, combination treatment significantly inhibited the growth of subcutaneous tumors in BALB/c nude mice and reduced the toxic side effects of DDP. Mechanistically, SB-HD and DDP combination treatment significantly promoted oxidative stress response, decreased MMP, inhibited ATP production, decreased ROS levels and increased SOD activity, increased the expression of NRF2, HO-1, ATG5 and LC3, decreased the expression of p62 and FTH1 both in OC cells and tumor tissue of mice. Inhibitor 3-MA (Methyladenine, autophagy inhibitor) and Fer-1 (Ferrostatin-1, iron ion inhibitor) can effectively reverse the expression changes of the key target proteins, but not ZnPP (Zinc protoporphyrin, HO-1 inhibitor). Through bioinformatics analysis, it was found that the abnormal expression level of NRF2 and FTH1 mRNA has a high prognostic value, at the same time, the other four key proteins respectively or interacting with NRF2 and FTH1, also play important roles in the occurrence and development of OC.

Conclusion: Our findings uncover a synergistic effect of SB-HD and DDP against OC through modulating oxidative stress via NRF2-FTH1 autophagic degradation pathway, which may provide an important theoretical foundation for the use of SB-HD and a new strategy for enhancing DDP chemosensitivity as well as reducing toxic side effects.

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来源期刊
Journal of Ovarian Research
Journal of Ovarian Research REPRODUCTIVE BIOLOGY-
CiteScore
6.20
自引率
2.50%
发文量
125
审稿时长
>12 weeks
期刊介绍: Journal of Ovarian Research is an open access, peer reviewed, online journal that aims to provide a forum for high-quality basic and clinical research on ovarian function, abnormalities, and cancer. The journal focuses on research that provides new insights into ovarian functions as well as prevention and treatment of diseases afflicting the organ. Topical areas include, but are not restricted to: Ovary development, hormone secretion and regulation Follicle growth and ovulation Infertility and Polycystic ovarian syndrome Regulation of pituitary and other biological functions by ovarian hormones Ovarian cancer, its prevention, diagnosis and treatment Drug development and screening Role of stem cells in ovary development and function.
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