Ota Akira, Tajima Masataka, Mori Kazunori, Sugiyama Erika, Sato Vilasinee Hirunpanich, Sato Hitoshi
Division of Pharmacokinetics and Pharmacodynamics, Department of Pharmacology, Toxicology and Therapeutics, School of Pharmacy, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan.
Division of Cancer Cell Biology, Department of Pharmaceutical Sciences, School of Pharmacy, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan.
Pharmacol Rep. 2021 Jun;73(3):847-857. doi: 10.1007/s43440-021-00260-0. Epub 2021 Apr 17.
Silver is a transition metal that is known to be less toxic than platinum. However, only few studies have reported the anticancer effects of some silver complexes and their possibility as an alternative to platinum complex. This study investigated the anticancer effects of the silver thiosulfate complex (STS), [Ag(SO)], consisting of silver and sodium thiosulfate.
In vitro cytotoxic activity of STS was investigated comparatively in human cancer cell lines (K562 and MCF-7) and normal human cells (mesenchymal stem cells and mammary epithelial cells). For its anticancer effects, cell cycle, mode of cell death, morphological changes, and accumulation of intracellular ROS and GSH were evaluated in MCF-7 to provide mechanistic insights.
STS showed a concentration-dependent cytotoxicity in MCF-7 cell, which was abolished by pretreatment with N-acetylcysteine, suggesting ROS accumulation by STS. Moreover, STS caused cell cycle arrest at the G1 phase, decrease in the GSH levels, and morphological changes in MCF-7. Direct measurement of ROS demonstrated the elevation of intracellular ROS accumulation in cancer cells treated with STS; however, neither cytotoxicity nor ROS accumulation was observed in normal human cells.
The results obtained here are the first evidence to show that STS exhibited an anticancer activity through ROS-induced mechanisms, and that its cytotoxicity is highly selective to cancer cells. The results of the present study warrant further investigation on the detailed mechanism of STS actions, as well as its in vivo effectiveness and safety for clinical application.
银是一种过渡金属，已知其毒性低于铂。然而，仅有少数研究报道了某些银配合物的抗癌作用及其作为铂配合物替代品的可能性。本研究调查了由银和硫代硫酸钠组成的硫代硫酸银配合物（STS），即[Ag(SO)]的抗癌作用。
比较研究了STS在人癌细胞系（K562和MCF-7）和正常人细胞（间充质干细胞和乳腺上皮细胞）中的体外细胞毒性活性。为探究其抗癌作用，在MCF-7细胞中评估了细胞周期、细胞死亡模式、形态变化以及细胞内活性氧（ROS）和谷胱甘肽（GSH）的积累情况以提供作用机制方面的见解。
STS在MCF-7细胞中表现出浓度依赖性细胞毒性，用N-乙酰半胱氨酸预处理可消除这种毒性，提示STS导致ROS积累。此外，STS使MCF-7细胞的细胞周期停滞在G1期，降低GSH水平并引起形态变化。直接测量ROS表明，用STS处理的癌细胞中细胞内ROS积累增加；然而，在正常人细胞中未观察到细胞毒性和ROS积累。
本研究结果首次证明STS通过ROS诱导机制发挥抗癌活性，且其细胞毒性对癌细胞具有高度选择性。本研究结果值得进一步研究STS作用的详细机制及其临床应用的体内有效性和安全性。
