Ginkgetin enhances breast cancer radiotherapy sensitization by suppressing NRF2-HO-1 axis activity.

IF 3.3 3区 医学 Q2 PHARMACOLOGY & PHARMACY
Qiong Duan, Zhenting Cui, Mingxiao Wang, Ruochen Li, Feng Han, Jianxin Ma
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Abstract

Breast cancer (BC) is a critical threat to women's lives. Radiotherapy (RT) is a pivotal treatment modality for BC, but the failure of RT due to radioresistance is still not well facilitated. Ginkgetin (GK) has a potent anti-tumor activity intimately associated with ferroptosis. This study applied in vitro and in vivo experimental models to ascertain the GK mechanism of action on BC radioresistance. The outcomes reported that GK could inhibit BC cell growth and increase apoptosis. In addition, when BC cells generated radioresistance, GK promoted ferroptosis of radioresistant BC cells by mitigating NRF2 expression, suppressing HO-1 and NQO1 expression, increasing the intracellular content of reactive oxygen species (ROS) and ferrous ions, accelerating the glutathione (GSH) depletion, and decreasing GPX4 expression. Notably, GK can damage intracellular mitochondria and cause a substantial increase in ferrous ions in BC cells. Therefore, GK shows immense potential for enhancing breast cancer radiotherapy sensitivity, which may provide pivotal evidence for subsequent RT sensitization.

银杏黄酮通过抑制 NRF2-HO-1 轴活性增强乳腺癌放疗的敏感性
乳腺癌(BC)是对女性生命的严重威胁。放射治疗(RT)是治疗BC的关键方式,但由于放射耐药的RT失败仍然不太容易。银杏苷(GK)具有与铁下垂密切相关的抗肿瘤活性。本研究采用体外和体内实验模型来确定GK对BC辐射耐药的作用机制。结果显示,GK可抑制BC细胞生长,增加凋亡。此外,当BC细胞产生辐射抗性时,GK通过减轻NRF2表达、抑制HO-1和NQO1表达、增加细胞内活性氧(ROS)和亚铁离子含量、加速谷胱甘肽(GSH)消耗、降低GPX4表达,促进了辐射抗性BC细胞的铁凋亡。值得注意的是,GK可以破坏细胞内线粒体,并导致BC细胞中铁离子的大量增加。因此,GK在增强乳腺癌放疗敏感性方面显示出巨大的潜力,这可能为后续的放疗增敏提供关键证据。
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来源期刊
CiteScore
6.80
自引率
2.60%
发文量
309
审稿时长
32 days
期刊介绍: Toxicology and Applied Pharmacology publishes original scientific research of relevance to animals or humans pertaining to the action of chemicals, drugs, or chemically-defined natural products. Regular articles address mechanistic approaches to physiological, pharmacologic, biochemical, cellular, or molecular understanding of toxicologic/pathologic lesions and to methods used to describe these responses. Safety Science articles address outstanding state-of-the-art preclinical and human translational characterization of drug and chemical safety employing cutting-edge science. Highly significant Regulatory Safety Science articles will also be considered in this category. Papers concerned with alternatives to the use of experimental animals are encouraged. Short articles report on high impact studies of broad interest to readers of TAAP that would benefit from rapid publication. These articles should contain no more than a combined total of four figures and tables. Authors should include in their cover letter the justification for consideration of their manuscript as a short article.
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