Departament of Bioinorganic Chemistry, Medical University of Lodz, Muszyńskiego 1, 90-151 Lodz, Poland.
Int J Mol Sci. 2021 Jul 15;22(14):7568. doi: 10.3390/ijms22147568.
Continuing our studies on the mechanisms underlying the cytotoxicity of potential drugs, we have described several aspects of the in vitro anticancer activity of ruthenium(II) and platinum(II) complexes with bioactive, synthetic aminoflavone ligands. We examined the mechanism of proapoptotic activity of -dichlorobis(3-imino-2-methoxyflavanone)ruthenium(II), -dichlorobis(3-imino-2-ethoxyflavanone)ruthenium(II), and -dichlorobis(3-aminoflavone)platinum(II). Cisplatin was used as a reference compound. The cytotoxicity was investigated by MTT assay. The mechanism of proapoptotic activity of the tested compounds was investigated by evaluation of caspase-8 activity, cytometric analysis of annexin-V positive cells, and mitochondrial potential loss measurement. The results showed that ruthenium compounds break partially or completely the cisplatin resistance by activating the caspase 8-dependent apoptosis pathway and loss of mitochondrial membrane potential. Platinum compounds also have a cytostatic effect, but their action requires more exposure time. Potential mechanisms underlying drug resistance in the two pairs of cancer cell lines were investigated: total glutathione content, P-glycoprotein activity, and differences in the activity of DNA repair induced by nucleotide excision. Results showed that cisplatin-resistant cells have elevated glutathione levels relative to sensitive cells. Moreover, they indicated the mechanisms enabling cells to avoid apoptosis caused by DNA damage. Pg-P activity has no effect on the development of cisplatin resistance in the cell lines described.
我们继续研究潜在药物细胞毒性的作用机制，描述了具有生物活性的合成氨基黄酮配体的钌(II)和铂(II)配合物的体外抗癌活性的几个方面。我们研究了 -二氯二（3-亚氨基-2-甲氧基黄酮）钌(II)、-二氯二（3-亚氨基-2-乙氧基黄酮）钌(II)和 -二氯二（3-氨基黄酮）铂(II)的促凋亡活性的机制。顺铂被用作参考化合物。通过 MTT 测定法研究了细胞毒性。通过评估半胱天冬酶-8 活性、流式细胞术分析膜联蛋白-V 阳性细胞以及线粒体膜电位损失测量来研究测试化合物的促凋亡活性的机制。结果表明，钌化合物通过激活半胱天冬酶 8 依赖性凋亡途径和线粒体膜电位丧失部分或完全打破顺铂耐药性。铂化合物也具有细胞抑制作用，但它们的作用需要更长的暴露时间。在两对癌细胞系中研究了药物耐药性的潜在机制：总谷胱甘肽含量、P-糖蛋白活性以及核苷酸切除诱导的 DNA 修复活性的差异。结果表明，与敏感细胞相比，顺铂耐药细胞的谷胱甘肽水平升高。此外，这些结果表明了使细胞能够避免由 DNA 损伤引起的细胞凋亡的机制。Pg-P 活性对所描述的细胞系中顺铂耐药性的发展没有影响。
