Anti-tumor effects of the eIF4A Inhibitor didesmethylrocaglamide and its derivatives in human and canine osteosarcomas

Inhibition of translation initiation using eIF4A inhibitors like (-)-didesmethylrocaglamide [(-)-DDR] and (-)-rocaglamide [(-)-Roc] is a potential cancer treatment strategy as they simultaneously diminish multiple oncogenic drivers. We showed that human and dog osteosarcoma cells expressed high levels of eIF4A1/2, which are important for cell growth. To advance preclinical development of eIF4A inhibitors, the importance of (-)-chirality in DDR for growth-inhibitory activity was demonstrated. Bromination of DDR at carbon-5 abolished growth-inhibitory activity, while acetylating DDR at carbon-1 was tolerated. Like DDR and Roc, DDR-acetate increased the ?H2A.X levels and induced G2/M arrest and apoptosis. These rocaglates decreased the levels of several mitogenic kinases, the STAT3 transcription factor, and the stress-activated protein kinase p38. However, phosphorylated p38 was greatly enhanced, implying activation of stress response pathways. Importantly, these rocaglates potently suppressed canine osteosarcoma patient-derived xenografts. These results suggest that these eIF4A inhibitors can be leveraged to treat both human and dog osteosarcomas. Overall design: RNA sequencing of MG-63 and Saos2 human osteosarcoma cells treated for 24 hours with DMSO or 1x growth-inhibitory IC50 of the eIF4A1/2 inhibitors rocaglamide (Roc) or didesmethylrocaglamide. MG-63 treatment was conducted as two biological replicates and Saos2 cells as three biological replicates.