Inhibition of Wnt/β-catenin by anthelmintic drug niclosamide effectively targets growth, survival, and angiogenesis of retinoblastoma.

Retinoblastoma is an angiogenesis-dependent ocular tumor, the clinical management of which remains a challenge. Agents that can target tumor cells and angiogenesis, as well as augment current chemotherapy efficacy, present a promising therapeutic strategy for retinoblastoma. We demonstrated that niclosamide, an FDA-approved anthelmintic drug, is effective against multiple aspects of retinoblastoma. Niclosamide inhibited proliferation via causing cell cycle arrest at the G2/M phase and induced caspase-dependent apoptosis in a panel of retinoblastoma cell lines, including Y79, RB116, and WERI-Rb-1. In addition, niclosamide inhibited retinoblastoma angiogenesis by disrupting capillary network formation, decreasing migration and proliferation, and inducing apoptosis of human primary retinal microvascular endothelial cells. We also demonstrated that niclosamide specifically suppresses the levels of p-LRP6, Dvl2, and β-catenin, but not p-STAT3, in Y79 cells. It decreased β-catenin activity and the mRNA expression levels of Wnt/β-catenin target genes. Stabilization of β-catenin with the Wnt activator lithium or overexpression of β-catenin reversed the inhibitory effects of niclosamide in Y79 cells, confirming Wnt/β-catenin as the molecular target of niclosamide in retinoblastoma cells. Importantly, niclosamide significantly enhanced the in vitro and in vivo efficacy of carboplatin and inhibited Wnt/β-catenin signaling in a retinoblastoma xenograft mouse model. Our data suggest that niclosamide is a promising candidate for the treatment armamentarium for retinoblastoma. Our work also highlights that targeting Wnt/β-catenin is a potential therapeutic strategy in retinoblastoma.