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Abstract
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 higher levels of eIF4A1/2 compared with mesenchymal stem cells. Genetic depletion of eIF4A1 and/or 2 slowed osteosarcoma cell growth. To advance preclinical development of eIF4A inhibitors, we demonstrated the importance of (−)-chirality in DDR for growth-inhibitory activity. Bromination of DDR at carbon-5 abolished growth-inhibitory activity, while acetylating DDR at carbon-1 was tolerated. Like (−)-DDR, (±)-DDR, and (−)-Roc, (±)-DDR-acetate increased γH2A.X levels and induced G2/M arrest and apoptosis. Consistent with translation inhibition, 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 in treated cells, suggesting activation of stress response pathways. RNA sequencing identified RHOB as a top upregulated gene in both (−)-DDR- and (−)-Roc-treated osteosarcoma cells, but the Rho inhibitor Rhosin did not enhance the growth-inhibitory activity of (−)-DDR or (−)-Roc. Nonetheless, these rocaglates potently suppressed tumor growth in a canine osteosarcoma patient-derived xenograft model. These results suggest that these eIF4A inhibitors can be leveraged to treat both human and dog osteosarcomas.
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1 Abigail Wexner Research Institute, Nationwide Children’s Hospital, Center for Childhood Cancer, Columbus, USA (GRID:grid.240344.5) (ISNI:0000 0004 0392 3476)
2 The Ohio State University College of Pharmacy, Division of Medicinal Chemistry and Pharmacognosy, Columbus, USA (GRID:grid.261331.4) (ISNI:0000 0001 2285 7943)
3 The Ohio State University, College of Veterinary Medicine, Columbus, USA (GRID:grid.261331.4) (ISNI:0000 0001 2285 7943); Ethos Veterinary Health and Ethos Discovery (501c3), Woburn, USA (GRID:grid.261331.4)
4 Abigail Wexner Research Institute, Nationwide Children’s Hospital, Center for Childhood Cancer, Columbus, USA (GRID:grid.240344.5) (ISNI:0000 0004 0392 3476); The Ohio State University College of Medicine, Departments of Pediatrics, Columbus, USA (GRID:grid.261331.4) (ISNI:0000 0001 2285 7943); The Ohio State University College of Medicine, Departments of Otolaryngology-Head & Neck Surgery, Columbus, USA (GRID:grid.261331.4) (ISNI:0000 0001 2285 7943); The Ohio State University College of Medicine, Departments of Pathology, Columbus, USA (GRID:grid.261331.4) (ISNI:0000 0001 2285 7943)