文章：

突变状态与葡萄糖可用性影响乳腺癌细胞对线粒体靶向槲皮素衍生物的反应

Mutation Status and Glucose Availability Affect the Response to Mitochondria-Targeted Quercetin Derivative in Breast Cancer Cells

原文发布日期：28 November 2023

DOI: 10.3390/cancers15235614

类型: Article

开放获取: 是

英文摘要：

Mitochondria, the main cellular power stations, are important modulators of redox-sensitive signaling pathways that may determine cell survival and cell death decisions. As mitochondrial function is essential for tumorigenesis and cancer progression, mitochondrial targeting has been proposed as an attractive anticancer strategy. In the present study, three mitochondria-targeted quercetin derivatives (mitQ3, 5, and 7) were synthesized and tested against six breast cancer cell lines with different mutation and receptor status, namely ER-positive MCF-7, HER2-positive SK-BR-3, and four triple-negative (TNBC) cells, i.e., MDA-MB-231, MDA-MB-468, BT-20, and Hs 578T cells. In general, the mito-quercetin response was modulated by the mutation status. In contrast to unmodified quercetin, 1 µM mitQ7 induced apoptosis in breast cancer cells. In MCF-7 cells, mitQ7-mediated apoptosis was potentiated under glucose-depleted conditions and was accompanied by elevated mitochondrial superoxide production, while AMPK activation-based energetic stress was associated with the alkalization of intracellular milieu and increased levels of NSUN4. Mito-quercetin also eliminated doxorubicin-induced senescent breast cancer cells, which was accompanied by the depolarization of mitochondrial transmembrane potential. Limited glucose availability also sensitized doxorubicin-induced senescent breast cancer cells to apoptosis. In conclusion, we show an increased cytotoxicity of mitochondria-targeted quercetin derivatives compared to unmodified quercetin against breast cancer cells with different mutation status that can be potentiated by modulating glucose availability.

摘要翻译： 

线粒体作为细胞的主要能量站，是调控氧化还原敏感信号通路的关键调节因子，这些通路可能决定细胞的存活与死亡命运。鉴于线粒体功能对肿瘤发生和癌症进展至关重要，靶向线粒体已被提出作为一种有前景的抗癌策略。本研究合成了三种线粒体靶向槲皮素衍生物（mitQ3、mitQ5和mitQ7），并测试了其对六种具有不同突变和受体状态的乳腺癌细胞系的作用，包括ER阳性MCF-7细胞、HER2阳性SK-BR-3细胞以及四种三阴性乳腺癌（TNBC）细胞（即MDA-MB-231、MDA-MB-468、BT-20和Hs 578T细胞）。总体而言，线粒体靶向槲皮素的反应受突变状态调控。与未修饰的槲皮素相比，1 µM mitQ7能诱导乳腺癌细胞凋亡。在MCF-7细胞中，mitQ7介导的凋亡在葡萄糖耗竭条件下增强，并伴随线粒体超氧化物产生增加，而基于AMPK激活的能量应激则与细胞内环境碱化及NSUN4水平升高相关。线粒体靶向槲皮素还能清除阿霉素诱导的衰老乳腺癌细胞，这一过程伴随线粒体跨膜电位去极化。有限的葡萄糖可用性也增强了阿霉素诱导的衰老乳腺癌细胞对凋亡的敏感性。总之，本研究表明，与未修饰的槲皮素相比，线粒体靶向槲皮素衍生物对不同突变状态的乳腺癌细胞具有更强的细胞毒性，且这种毒性可通过调节葡萄糖可用性进一步增强。

原文链接：

Mutation Status and Glucose Availability Affect the Response to Mitochondria-Targeted Quercetin Derivative in Breast Cancer Cells