使用 (-)-二去甲基罗卡酰胺 [(-)-DDR] 和 (-)-罗卡酰胺 [(-)-Roc] 等 eIF4A 抑制剂抑制翻译起始是一种潜在的癌症治疗策略，因为它们同时消除多种致癌驱动因素。我们发现，与间充质干细胞相比，人类和狗的骨肉瘤细胞表达更高水平的 eIF4A1/2。 eIF4A1 和/或 2 的基因缺失会减缓骨肉瘤细胞的生长。为了推进 eIF4A 抑制剂的临床前开发，我们证明了 DDR 中 (-)-手性对于生长抑制活性的重要性。 DDR 在碳 5 处的溴化消除了生长抑制活性，而在碳 1 处乙酰化 DDR 是可以耐受的。与 (-)-DDR、(±)-DDR 和 (-)-Roc 一样，(±)-DDR-乙酸盐增加 γH2A.X 水平并诱导 G2/M 停滞和细胞凋亡。与翻译抑制一致，这些 rocaglalate 降低了几种有丝分裂激酶、STAT3 转录因子和应激激活蛋白激酶 p38 的水平。然而，磷酸化的 p38 在处理的细胞中大大增强，表明应激反应途径被激活。 RNA 测序鉴定 RHOB 是 (-)-DDR 和 (-)-Roc 处理的骨肉瘤细胞中最上调的基因，但 Rho 抑制剂 Rhosin 并未增强 (-)-DDR 或 (-)-DDR 或 (-)-Roc 的生长抑制活性。 ）-鹏。尽管如此，这些罗卡格拉酯在犬骨肉瘤患者来源的异种移植模型中有效抑制了肿瘤生长。这些结果表明这些 eIF4A 抑制剂可用于治疗人类和狗的骨肉瘤。© 2024。作者。

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.© 2024. The Author(s).