Wedelolactone induces apoptosis and pyroptosis in retinoblastoma through promoting ROS generation

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.