Jangili Paramesh, Kong Na, Kim Ji Hyeon, Zhou Jun, Liu Haijun, Zhang Xingcai, Tao Wei, Kim Jong Seung
Department of Chemistry, Korea University, Seoul, 02841, Korea.
Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, Zhejiang, 311121, China.
Angew Chem Int Ed Engl. 2022 Apr 11;61(16):e202117075. doi: 10.1002/anie.202117075. Epub 2022 Feb 19.
We report a novel multifunctional construct, M1, designed explicitly to target the DNA damage response in cancer cells. M1 contains both a floxuridine (FUDR) and protein phosphatase 2A (PP2A) inhibitor combined with a GSH-sensitive linker. Further conjugation of the triphenylphosphonium moiety allows M1 to undergo specific activation in the mitochondria, where mitochondria-mediated apoptosis is observed. Moreover, M1 has enormous effects on genomic DNA ascribed to FUDR's primary function of impeding DNA/RNA synthesis combined with diminishing PP2A-activated DNA repair pathways. Importantly, mechanistic studies highlight the PP2A obtrusion in FUDR/5-fluorouracil (5-FU) therapy and underscore the importance of its inhibition to harbor therapeutic potential. HCT116 cell xenograft-bearing mice that have a low response rate to 5-FU show a prominent effect with M1, emphasizing the importance of DNA damage response targeting strategies using tumor-specific microenvironment-activatable systems.
我们报告了一种新型多功能构建体M1，其专门设计用于靶向癌细胞中的DNA损伤反应。M1包含氟尿苷（FUDR）和蛋白磷酸酶2A（PP2A）抑制剂，并与谷胱甘肽敏感连接子结合。三苯基鏻部分的进一步缀合使M1能够在线粒体中进行特异性激活，在那里观察到线粒体介导的细胞凋亡。此外，由于FUDR阻碍DNA/RNA合成的主要功能以及减少PP2A激活的DNA修复途径，M1对基因组DNA有巨大影响。重要的是，机制研究突出了PP2A在FUDR/5-氟尿嘧啶（5-FU）治疗中的干扰作用，并强调了抑制PP2A以发挥治疗潜力的重要性。对5-FU反应率低的携带HCT116细胞异种移植瘤的小鼠对M1表现出显著效果。这强调了使用肿瘤特异性微环境可激活系统的DNA损伤反应靶向策略的重要性。
