Department of Surgery, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, 08903, USA.
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08901, USA.
Sci Rep. 2022 Jul 30;12(1):13135. doi: 10.1038/s41598-022-17446-y.
The imidazolium compound Ym155 was first reported to be a survivin inhibitor. Ym155 potently induces cell death of many types of cancer cells in preclinical studies. However, in phase II clinical trials Ym155 failed to demonstrate a significant benefit. Studies have suggested that the cytotoxic effects of Ym155 in cancer cells are not mediated by the inhibition of survivin. Understanding the mechanism by which Ym155 induces cell death would provide important insight how to improve its efficacy as a cancer therapeutic. We demonstrate a novel mechanism by which Ym155 induces cell death by localizing to the mitochondria causing mitochondrial dysfunction. Our studies suggest that Ym155 binds mitochondrial DNA leading to a decrease in oxidative phosphorylation, decrease in TCA cycle intermediates, and an increase in mitochondrial permeability. Furthermore, we show that mitochondrial stress induced by Ym155 and other mitochondrial inhibitors activates AMP-activated kinase leading to the downregulation to bone morphogenetic protein (BMP) signaling. We provide first evidence that Ym155 initiates cell death by disrupting mitochondrial function.
咪唑化合物 Ym155 最初被报道为一种生存素抑制剂。在临床前研究中，Ym155 强烈诱导多种类型的癌细胞死亡。然而，在 II 期临床试验中，Ym155 未能显示出显著的益处。研究表明，Ym155 在癌细胞中的细胞毒性作用不是通过抑制生存素介导的。了解 Ym155 诱导细胞死亡的机制将为如何提高其作为癌症治疗药物的疗效提供重要的见解。我们证明了一种通过定位于线粒体导致线粒体功能障碍来诱导细胞死亡的新机制。我们的研究表明，Ym155 结合线粒体 DNA，导致氧化磷酸化减少、三羧酸循环中间产物减少和线粒体通透性增加。此外，我们还表明，Ym155 和其他线粒体抑制剂引起的线粒体应激激活 AMP 激活的蛋白激酶，导致骨形态发生蛋白（BMP）信号转导下调。我们提供了第一个证据表明，Ym155 通过破坏线粒体功能引发细胞死亡。
