Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Str. 42, 1090, Vienna, Austria.
Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Str. 38, 1090, Vienna, Austria.
Angew Chem Int Ed Engl. 2021 Mar 1;60(10):5063-5068. doi: 10.1002/anie.202015962. Epub 2021 Feb 1.
The ruthenium-based anticancer agent BOLD-100/KP1339 has shown promising results in several in vitro and in vivo tumour models as well as in early clinical trials. However, its mode of action remains to be fully elucidated. Recent evidence identified stress induction in the endoplasmic reticulum (ER) and concomitant down-modulation of HSPA5 (GRP78) as key drug effects. By exploiting the naturally formed adduct between BOLD-100 and human serum albumin as an immobilization strategy, we were able to perform target-profiling experiments that revealed the ribosomal proteins RPL10, RPL24, and the transcription factor GTF2I as potential interactors of this ruthenium(III) anticancer agent. Integrating these findings with proteomic profiling and transcriptomic experiments supported ribosomal disturbance and concomitant induction of ER stress. The formation of polyribosomes and ER swelling of treated cancer cells revealed by TEM validated this finding. Thus, the direct interaction of BOLD-100 with ribosomal proteins seems to accompany ER stress-induction and modulation of GRP78 in cancer cells.
基于钌的抗癌剂 BOLD-100/KP1339 在几种体外和体内肿瘤模型以及早期临床试验中显示出有希望的结果。然而，其作用模式仍有待充分阐明。最近的证据表明内质网（ER）中的应激诱导以及同时下调 HSPA5（GRP78）是关键的药物作用。通过利用 BOLD-100 与人血清白蛋白之间自然形成的加合物作为固定化策略，我们能够进行靶向分析实验，揭示核糖体蛋白 RPL10、RPL24 和转录因子 GTF2I 是这种三价钌抗癌剂的潜在相互作用物。将这些发现与蛋白质组学和转录组学实验相结合，支持核糖体紊乱和同时诱导 ER 应激。TEM 观察到处理后的癌细胞中多核糖体的形成和 ER 肿胀证实了这一发现。因此，BOLD-100 与核糖体蛋白的直接相互作用似乎伴随着 ER 应激诱导和 GRP78 在癌细胞中的调节。
