ROS, Apoptosis and Cancer Biology Laboratory, Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
Cell Death Dis. 2013 Jun 6;4(6):e653. doi: 10.1038/cddis.2013.185.
Engagement of the mitochondrial-death amplification pathway is an essential component in chemotherapeutic execution of cancer cells. Therefore, identification of mitochondria-targeting agents has become an attractive avenue for novel drug discovery. Here, we report the anticancer activity of a novel Osmium-based organometallic compound (hereafter named Os) on different colorectal carcinoma cell lines. HCT116 cell line was highly sensitive to Os and displayed characteristic features of autophagy and apoptosis; however, inhibition of autophagy did not rescue cell death unlike the pan-caspase inhibitor z-VAD-fmk. Furthermore, Os significantly altered mitochondrial morphology, disrupted electron transport flux, decreased mitochondrial transmembrane potential and ATP levels, and triggered a significant increase in reactive oxygen species (ROS) production. Interestingly, the sensitivity of cell lines to Os was linked to its ability to induce mitochondrial ROS production (HCT116 and RKO) as HT29 and SW620 cell lines that failed to show an increase in ROS were resistant to the death-inducing activity of Os. Finally, intra-peritoneal injections of Os significantly inhibited tumor formation in a murine model of HCT116 carcinogenesis, and pretreatment with Os significantly enhanced tumor cell sensitivity to cisplatin and doxorubicin. These data highlight the mitochondria-targeting activity of this novel compound with potent anticancer effect in vitro and in vivo, which could have potential implications for strategic therapeutic drug design.
线粒体死亡放大途径的参与是癌细胞化疗执行的一个重要组成部分。因此，鉴定线粒体靶向剂已成为新药物发现的一个有吸引力的途径。在这里，我们报告了一种新型基于锇的有机金属化合物（以下简称 Os）对不同结直肠癌细胞系的抗癌活性。HCT116 细胞系对 Os 高度敏感，并显示出自噬和细胞凋亡的特征；然而，与泛半胱天冬酶抑制剂 z-VAD-fmk 不同，自噬的抑制并没有挽救细胞死亡。此外，Os 显著改变线粒体形态，破坏电子传递通量，降低线粒体跨膜电位和 ATP 水平，并引发活性氧（ROS）产生的显著增加。有趣的是，细胞系对 Os 的敏感性与其诱导线粒体 ROS 产生的能力有关（HCT116 和 RKO），因为 HT29 和 SW620 细胞系未能显示 ROS 增加，对 Os 的诱导细胞死亡活性具有抗性。最后，腹腔内注射 Os 显著抑制了 HCT116 致癌小鼠模型中的肿瘤形成，而 Os 的预处理显著增强了肿瘤细胞对顺铂和阿霉素的敏感性。这些数据突出了这种新型化合物的线粒体靶向活性，具有体外和体内强大的抗癌作用，这可能对战略性治疗药物设计具有潜在意义。
