Department of Hematology, Changzheng Hospital, Second Military Medical University, Shanghai 201203, China; National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Cancer Lett. 2015 May 1;360(2):257-68. doi: 10.1016/j.canlet.2015.02.029. Epub 2015 Feb 23.
Identifying chemotherapy candidates with high selectivity against cancer cells is a major challenge in cancer treatment. Tumor microenvironments cause chronic endoplasmic reticulum (ER) stress and activate the unfolded protein response (UPR) as an adaptive response. Here, one novel small-molecule compound, 17#, was discovered as a potent pan-UPR inhibitor. It exhibited good selection for growth inhibition when cancer cells were cultured in 2-deoxy-D-glucose (2DG), mimicking an in vitro glucose-deprived status. Additionally, 17# alone could mildly suppress the growth of HeLa tumor xenografts, and a synergistic anti-cancer effect was observed when 17# was combined with 2DG. A mechanistic study showed that 17#-induced selective anti-cancer effects were highly dependent on UPR inhibition, and overexpressing GRP78 or XBP1s reversed the 17#-induced growth inhibition and cell cycle arrest, partially by delaying the downregulation of the cell cycle regulator cyclin B1. Furthermore, 17# improved the sensitivity of anti-cancer drugs such as doxorubicin or etoposide. Our study presents evidence that disrupting the UPR has selective therapeutic potential and may enhance drug sensitivity.
鉴定对癌细胞具有高选择性的化疗药物是癌症治疗的一大挑战。肿瘤微环境会导致慢性内质网（ER）应激，并激活未折叠蛋白反应（UPR）作为一种适应性反应。在这里，我们发现了一种新型小分子化合物 17#，它是一种有效的泛 UPR 抑制剂。当癌细胞在 2-脱氧-D-葡萄糖（2DG）中培养时，模拟体外葡萄糖剥夺状态，它表现出对生长抑制的良好选择性。此外，17# 单独使用时可以轻度抑制 HeLa 肿瘤异种移植物的生长，并且当 17# 与 2DG 联合使用时观察到协同的抗癌作用。机制研究表明，17# 诱导的选择性抗癌作用高度依赖于 UPR 抑制，过表达 GRP78 或 XBP1s 可逆转 17# 诱导的生长抑制和细胞周期停滞，部分原因是延迟细胞周期调节剂细胞周期蛋白 B1 的下调。此外，17# 提高了多柔比星或依托泊苷等抗癌药物的敏感性。我们的研究表明，破坏 UPR 具有选择性的治疗潜力，并可能提高药物敏感性。
