文章：

新型噻吩并嘧啶-肼基化合物在三阴性乳腺癌细胞中诱导DRP1介导的非凋亡性细胞死亡

Novel Thienopyrimidine-Hydrazinyl Compounds Induce DRP1-Mediated Non-Apoptotic Cell Death in Triple-Negative Breast Cancer Cells

原文发布日期：23 July 2024

DOI: 10.3390/cancers16152621

类型: Article

开放获取: 是

英文摘要：

Apoptosis induction with taxanes or anthracyclines is the primary therapy for TNBC. Cancer cells can develop resistance to anticancer drugs, causing them to recur and metastasize. Therefore, non-apoptotic cell death inducers could be a potential treatment to circumvent apoptotic drug resistance. In this study, we discovered two novel compounds, TPH104c and TPH104m, which induced non-apoptotic cell death in TNBC cells. These lead compounds were 15- to 30-fold more selective in TNBC cell lines and significantly decreased the proliferation of TNBC cells compared to that of normal mammary epithelial cell lines. TPH104c and TPH104m induced a unique type of non-apoptotic cell death, characterized by the absence of cellular shrinkage and the absence of nuclear fragmentation and apoptotic blebs. Although TPH104c and TPH104m induced the loss of the mitochondrial membrane potential, TPH104c- and TPH104m-induced cell death did not increase the levels of cytochrome c and intracellular reactive oxygen species (ROS) and caspase activation, and cell death was not rescued by incubating cells with the pan-caspase inhibitor, carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone (Z-VAD-FMK). Furthermore, TPH104c and TPH104m significantly downregulated the expression of the mitochondrial fission protein, DRP1, and their levels determined their cytotoxic efficacy. Overall, TPH104c and TPH104m induced non-apoptotic cell death, and further determination of their cell death mechanisms will aid in the development of new potent and efficacious anticancer drugs to treat TNBC.

摘要翻译： 

紫杉烷类或蒽环类药物诱导的细胞凋亡是三阴性乳腺癌的主要治疗手段。癌细胞可对抗癌药物产生耐药性，导致肿瘤复发和转移。因此，非凋亡性细胞死亡诱导剂可能成为克服凋亡耐药性的潜在治疗策略。本研究发现了两种新型化合物TPH104c和TPH104m，能够诱导三阴性乳腺癌细胞发生非凋亡性细胞死亡。与正常乳腺上皮细胞系相比，这两种先导化合物对三阴性乳腺癌细胞系的选择性高出15-30倍，并显著抑制三阴性乳腺癌细胞增殖。TPH104c和TPH104m诱导的非凋亡性细胞死亡具有独特特征：无细胞皱缩、无核碎裂及凋亡小体形成。尽管TPH104c和TPH104m诱导线粒体膜电位丧失，但其诱导的细胞死亡并未增加细胞色素c水平、细胞内活性氧水平及半胱天冬酶活性，且广谱半胱天冬酶抑制剂Z-VAD-FMK未能挽救细胞死亡。此外，TPH104c和TPH104m显著下调线粒体分裂蛋白DRP1的表达水平，且该蛋白表达水平决定其细胞毒效价。综上所述，TPH104c和TPH104m可诱导非凋亡性细胞死亡，进一步阐明其细胞死亡机制将有助于开发治疗三阴性乳腺癌的新型高效抗癌药物。

原文链接：

Novel Thienopyrimidine-Hydrazinyl Compounds Induce DRP1-Mediated Non-Apoptotic Cell Death in Triple-Negative Breast Cancer Cells