Yukimura Tomona, Seki Tomohiro, Seki Toshinobu
Faculty of Pharmacy and Pharmaceutical Sciences, Josai University, 1-1 Keyakidai, Sakado, Saitama 350-0295, Japan.
Int J Mol Sci. 2025 Apr 26;26(9):4128. doi: 10.3390/ijms26094128.
GSH biosynthesis is enhanced in cancer cells that express the variant isoform of the surface antigen CD44 (CD44v), which is overexpressed in certain types of cancer. The GSH-responsive prodrug Ns-Dox was prepared by modifying the GSH-responsive group 2-nitrobenzene sulfonyl (Ns) with the model drug doxorubicin (Dox). Its function was evaluated based on its molecular interaction with model DNA in terms of its binding constant (). The association constant of Ns-Dox was lower, and its interaction with model DNA was weaker compared to that of Dox, suggesting that Ns-Dox may act as a less toxic prodrug. HCT116 cells with high CD44v expression and GSH levels and BT474 cells with low CD44v expression and GSH levels were used. The addition of Ns-Dox to HCT116 cells produced cytotoxic effects similar to those of Dox. In contrast, a significant difference in viability was observed between Ns-Dox- and Dox-treated BT474 cells at low concentrations. These findings suggest that Ns-Dox functions as a prodrug with low environmental toxicity and a lower GSH concentration in cancer cells. It is efficiently activated to Dox in cells with high GSH production, demonstrating its cell-killing effects.
在表达表面抗原CD44变异体同工型（CD44v）的癌细胞中，谷胱甘肽（GSH）生物合成增强，而CD44v在某些类型的癌症中过度表达。通过用模型药物阿霉素（Dox）修饰GSH响应基团2-硝基苯磺酰基（Ns），制备了GSH响应前药Ns-Dox。根据其与模型DNA的分子相互作用及其结合常数（）评估了它的功能。与Dox相比，Ns-Dox的缔合常数较低，其与模型DNA的相互作用较弱，这表明Ns-Dox可能是一种毒性较小的前药。使用了CD44v高表达和GSH水平高的HCT116细胞以及CD44v低表达和GSH水平低的BT474细胞。向HCT116细胞中添加Ns-Dox产生的细胞毒性作用与Dox相似。相比之下，在低浓度下，Ns-Dox处理的BT474细胞和Dox处理的BT474细胞之间的活力存在显著差异。这些发现表明，Ns-Dox作为一种前药，在癌细胞中具有低环境毒性和较低的GSH浓度。它在GSH产生高的细胞中被有效激活为Dox，显示出其细胞杀伤作用。
