Center for Childhood Cancer, Abigail Wexner Research Institute, Nationwide Children's Hospital, 575 Children's Crossroad, Columbus, OH, 43215, USA.
Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University College of Pharmacy, Columbus, OH, 43210, USA.
Sci Rep. 2024 Aug 20;14(1):19349. doi: 10.1038/s41598-024-69171-3.
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 G/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.
使用 eIF4A 抑制剂（如 (-)-didesmethylrocaglamide [(-)-DDR] 和 (-)-rocaglamide [(-)-Roc]）抑制翻译起始是一种潜在的癌症治疗策略，因为它们可以同时减少多种致癌驱动因素。我们表明，人源和犬源骨肉瘤细胞表达的 eIF4A1/2 水平高于间充质干细胞。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 (-)-chirality 在 DDR 中对生长抑制活性的重要性。DDR 碳-5 位溴化会使其丧失生长抑制活性，而碳-1 位乙酰化则可耐受。与 (-)-DDR 一样，(±)-DDR 和 (-)-Roc，(±)-DDR-acetate 也能增加 γH2A.X 水平，并诱导 G/M 期阻滞和细胞凋亡。与翻译抑制一致，这些 rocaglates 降低了几种有丝分裂原激酶、STAT3 转录因子和应激激活蛋白激酶 p38 的水平。然而，在用药物处理的细胞中，磷酸化的 p38 大大增强，表明应激反应途径被激活。RNA 测序确定 RHOB 是 (-)-DDR 和 (-)-Roc 处理的骨肉瘤细胞中上调最显著的基因之一，但 Rho 抑制剂 Rhosin 并没有增强 (-)-DDR 或 (-)-Roc 的生长抑制活性。尽管如此，这些 rocaglates 在犬源骨肉瘤患者来源的异种移植模型中仍能强力抑制肿瘤生长。这些结果表明，这些 eIF4A 抑制剂可用于治疗人和犬的骨肉瘤。
