Targeting eIF4E inhibits growth, survival and angiogenesis in retinoblastoma and enhances efficacy of chemotherapy.

Although the eukaryotic translation initiation factor 4E (eIF4E) has been shown to be critically involved in the transformation and progression of various tumors, little is known about the role of eIF4E in retinoblastoma. In this work, we report that ribavirin, a pharmacologic inhibitor of eIF4E function, effectively targets retinoblastoma and angiogenesis. Ribavirin treatment dose-dependently blocked the growth and stimulated apoptosis in various retinoblastoma cell lines, with IC50 values that are within the clinically achievable range. Ribavirin also significantly inhibited angiogenesis via disrupting capillary network formation and suppressing VEGF-induced migration, proliferation and survival of human retinal endothelial cells. In addition, ribavirin significantly augments chemotherapy agent's inhibitory effects in retinoblastoma in vitro and in vivo. Mechanistically, ribavirin inhibited eIF4E function in retinoblastoma cells as shown by the decreased protein levels of Cyclin D1, c-Myc and VEGF without affecting their mRNA expression. Overexpression of the wildtype and phosphormimetic but not the nonphosphorylatable form of eIF4E significantly abolished the inhibitory effects of ribavirin, further demonstrating eIF4E as the target of ribavirin. Genetic knockdown of eIF4E using two independent siRNAs mirrored ribavirin's effects, confirming the role of eIF4E in retinoblastoma growth, survival and response to chemotherapy. Our findings provide a preclinical rationale to explore ribavirin as a strategy to treat retinoblastoma and highlight the therapeutic value of targeting eIF4E in retinoblastoma.

Inhibition of Wnt/ß-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 ß-catenin, but not p-STAT3, in Y79 cells. It decreased ß-catenin activity and the mRNA expression levels of Wnt/ß-catenin target genes. Stabilization of ß-catenin with the Wnt activator lithium or overexpression of ß-catenin reversed the inhibitory effects of niclosamide in Y79 cells, confirming Wnt/ß-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/ß-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/ß-catenin is a potential therapeutic strategy in retinoblastoma.