Faculty of Chemistry, University of Wroclaw, Joliot-Curie 14, 50-383, Wroclaw, Poland.
Małopolska Center of Biotechnology, Jagiellonian University, Gronostajowa 7A, 30-387, Kraków, Poland.
Sci Rep. 2021 Dec 14;11(1):23943. doi: 10.1038/s41598-021-03352-2.
[CuI(2,9-dimethyl-1,10-phenanthroline)P(p-OCH-Ph)CHSarcosineGlycine] (1-MPSG), highly stable in physiological media phosphino copper(I) complex-is proposed herein as a viable alternative to anticancer platinum-based drugs. It is noteworthy that, 1-MPSG significantly and selectively reduced cell viability in a 3D spheroidal model of human lung adenocarcinoma (A549), in comparison with non-cancerous HaCaT cells. Confocal microscopy and an ICP-MS analysis showed that 1-MPSG effectively accumulates inside A549 cells with colocalization in mitochondria and nuclei. A precise cytometric analysis revealed a predominance of apoptosis over the other types of cell death. In the case of HaCaT cells, the overall cytotoxicity was significantly lower, indicating the selective activity of 1-MPSG towards cancer cells. Apoptosis also manifested itself in a decrease in mitochondrial membrane potential along with the activation of caspases-3/9. Moreover, the caspase inhibitor (Z-VAD-FMK) pretreatment led to decreased level of apoptosis (more pronouncedly in A549 cells than in non-cancerous HaCaT cells) and further validated the caspases dependence in 1-MPSG-induced apoptosis. Furthermore, the 1-MPSG complex presumably induces the changes in the cell cycle leading to G2/M phase arrest in a dose-dependent manner. It was also observed that the 1-MPSG mediated intracellular ROS alterations in A549 and HaCaT cells. These results, proved by fluorescence spectroscopy, and flow cytometry, suggest that investigated Cu(I) compound may trigger apoptosis also through ROS generation.
[CuI(2,9-二甲基-1,10-菲咯啉)P(p-OCH-Ph)CHSarcosineGlycine]（1-MPSG），在生理介质中具有高度稳定性的膦铜（I）配合物，被提出作为抗癌铂类药物的可行替代品。值得注意的是，与非癌细胞 HaCaT 相比，1-MPSG 在人肺腺癌细胞（A549）的 3D 球体模型中显著且选择性地降低了细胞活力。共焦显微镜和 ICP-MS 分析表明，1-MPSG 有效地在 A549 细胞内积累，与线粒体和细胞核共定位。精确的细胞计量分析显示，细胞凋亡占主导地位，而其他类型的细胞死亡则较少。在 HaCaT 细胞中，整体细胞毒性明显较低，表明 1-MPSG 对癌细胞具有选择性活性。细胞凋亡还表现为线粒体膜电位降低，同时激活 caspase-3/9。此外，用 caspase 抑制剂（Z-VAD-FMK）预处理会导致凋亡水平降低（在 A549 细胞中比在非癌细胞 HaCaT 细胞中更为明显），进一步验证了 caspase 在 1-MPSG 诱导的凋亡中的依赖性。此外，1-MPSG 配合物可能会导致细胞周期发生变化，以剂量依赖的方式导致 G2/M 期阻滞。还观察到 1-MPSG 介导的 A549 和 HaCaT 细胞内 ROS 改变。这些结果通过荧光光谱法和流式细胞术证明，表明所研究的 Cu(I)化合物可能通过 ROS 生成引发细胞凋亡。
