Anti-tumor Effects of the eIF4A Inhibitor Didesmethylrocaglamide and Its Derivatives in Human and Canine Osteosarcomas

TL;DR

This study shows that eIF4A inhibitors like DDR and its derivatives can effectively slow the growth of human and canine osteosarcomas by targeting multiple cancer-related pathways.

Contribution

The study identifies the importance of (−)-chirality in DDR and demonstrates the anti-tumor effects of eIF4A inhibitors in both human and canine osteosarcomas.

Findings

DDR and its derivatives inhibit osteosarcoma cell growth by reducing eIF4A1/2 levels and inducing apoptosis.

Phosphorylated p38 levels increase in treated cells, indicating activation of stress response pathways.

DDR and Roc potently suppress tumor growth in a canine osteosarcoma xenograft model.

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 high levels of eIF4A1/2, particularly eIF4A2. 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 and Roc, DDR-acetate increased the 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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