Department of Interventional Radiology and Vascular, The Affiliated Hospital of Guangzhou Medical University, Guangzhou Women and Children's Medical Center, Guangzhou 510060, China.
Department of Interventional Radiology and Vascular, The Affiliated Hospital of Guangzhou Medical University, Guangzhou Women and Children's Medical Center, Guangzhou 510060, China.
Int Immunopharmacol. 2022 Oct;111:108855. doi: 10.1016/j.intimp.2022.108855. Epub 2022 Jul 26.
Retinoblastoma is a most frequently occurring primary intraocular tumor in infancy and children, highlighting the requirement to find and develop novel and more effective therapeutic approaches. Wedelolactone (WDL), a nature compound isolated from E. prostrata, exhibits multiple biological activities through regulating various signaling pathways; however, its potential influences on retinoblastoma progression are still unknown, and thus was investigated in our study, as well as the underlying mechanisms. Here, we found that WDL treatments significantly reduced the proliferation of retinoblastoma cells by inducing apoptosis and pyroptosis through increasing Caspase-3, Caspase-1, gasdermin E (GSDME) and gasdermin D (GSDMD) activation. Mitochondrial impairment and reactive oxygen species (ROS) generation were considerably up-regulated in WDL-incubated retinoblastoma cells through a dose-dependent manner. Notably, we found that ROS scavenge significantly abolished the function of WDL to provoke apoptosis and pyroptosis in retinoblastoma cell lines, revealing that ROS was required for WDL to perform its anti-cancer role in retinoblastoma. Moreover, our in vivo experiments indicated that WDL administration significantly reduced the tumor growth in the established retinoblastoma mouse models with undetectable toxicity. Collectively, these findings highlighted the potential of WDL to inhibit the growth and induce cell death of retinoblastoma in vitro and in vivo, and thereby showed promise as a therapeutic agent for the treatment of retinoblastoma.
视网膜母细胞瘤是婴儿和儿童中最常见的原发性眼内肿瘤，这凸显了寻找和开发新型、更有效的治疗方法的必要性。韦德尔内酯（WDL）是从 E. prostrata 中分离出来的一种天然化合物，通过调节多种信号通路表现出多种生物学活性；然而，其对视网膜母细胞瘤进展的潜在影响尚不清楚，因此本研究对其进行了研究，并探讨了其潜在机制。在这里，我们发现 WDL 处理通过增加 Caspase-3、Caspase-1、gasdermin E (GSDME) 和 gasdermin D (GSDMD) 的激活，显著通过诱导细胞凋亡和细胞焦亡来抑制视网膜母细胞瘤细胞的增殖。WDL 孵育的视网膜母细胞瘤细胞中的线粒体损伤和活性氧（ROS）生成通过剂量依赖性方式显著上调。值得注意的是，我们发现 ROS 清除剂显著消除了 WDL 引发视网膜母细胞瘤细胞系凋亡和细胞焦亡的功能，表明 ROS 是 WDL 发挥其在视网膜母细胞瘤中的抗癌作用所必需的。此外，我们的体内实验表明，WDL 给药可显著减少已建立的视网膜母细胞瘤小鼠模型中的肿瘤生长，且无毒性。总之，这些发现强调了 WDL 抑制体外和体内视网膜母细胞瘤生长和诱导细胞死亡的潜力，因此有望成为治疗视网膜母细胞瘤的治疗剂。
