Malignant peripheral nerve sheath tumors (MPNST) frequently overexpress eukaryotic initiation factor 4F components, and the eIF4A inhibitor silvestrol potently suppresses MPNST growth. However, silvestrol has suboptimal drug-like properties, including a bulky structure, poor oral bioavailability (<2%), sensitivity to MDR1 efflux, and pulmonary toxicity in dogs. We compared ten silvestrol-related rocaglates lacking the dioxanyl ring and found that didesmethylrocaglamide (DDR) and rocaglamide (Roc) had growth-inhibitory activity comparable with silvestrol. Structure–activity relationship analysis revealed that the dioxanyl ring present in silvestrol was dispensable for, but may enhance, cytotoxicity. Both DDR and Roc arrested MPNST cells at G2–M, increased the sub-G1 population, induced cleavage of caspases and PARP, and elevated the levels of the DNA-damage response marker γH2A.X, while decreasing the expression of AKT and ERK1/2, consistent with translation inhibition. Unlike silvestrol, DDR and Roc were not sensitive to MDR1 inhibition. Pharmacokinetic analysis confirmed that Roc had 50% oral bioavailability. Importantly, Roc, when administered intraperitoneally or orally, showed potent antitumor effects in an orthotopic MPNST mouse model and did not induce pulmonary toxicity in dogs as found with silvestrol. Treated tumors displayed degenerative changes and had more cleaved caspase-3–positive cells, indicative of increased apoptosis. Furthermore, Roc effectively suppressed the growth of osteosarcoma, Ewing sarcoma, and rhabdomyosarcoma cells and patient-derived xenografts. Both Roc- and DDR-treated sarcoma cells showed decreased levels of multiple oncogenic kinases, including insulin-like growth factor-1 receptor. The more favorable drug-like properties of DDR and Roc and the potent antitumor activity of Roc suggest that these rocaglamides could become viable treatments for MPNST and other sarcomas.

中文翻译：

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rocaglamide 和 didesmethylrocaglamide 靶向蛋白质翻译治疗 MPNST 和其他肉瘤

恶性外周神经鞘瘤 (MPNST) 经常过度表达真核起始因子 4F 成分，而 eIF4A 抑制剂 silvestrol 有效抑制 MPNST 生长。然而，silvestrol 具有次优的药物样特性，包括庞大的结构、较差的口服生物利用度 (<2%)、对 MDR1 流出的敏感性以及对狗的肺毒性。我们比较了 10 种缺乏二恶烷基环的 silvestrol 相关 rocaglates，发现二去甲基罗格列胺 (DDR) 和 rocaglamide (Roc) 具有与 silvestrol 相当的生长抑制活性。结构-活性关系分析表明，西维雌醇中存在的二恶烷基环对于细胞毒性而言是可有可无的，但可能会增强细胞毒性。DDR 和 Roc 都在 G2–M 时阻止 MPNST 细胞，增加亚 G1 细胞群，诱导半胱天冬酶和 PARP 的裂解，并提高 DNA 损伤反应标记 γH2A.X 的水平，同时降低 AKT 和 ERK1/2 的表达，这与翻译抑制一致。与 silvestrol 不同，DDR 和 Roc 对 MDR1 抑制不敏感。药代动力学分析证实，Roc 具有 50% 的口服生物利用度。重要的是，当腹膜内或口服给药时，Roc 在原位 MPNST 小鼠模型中显示出有效的抗肿瘤作用，并且不会像西维雌醇那样在狗中引起肺毒性。治疗后的肿瘤显示出退行性变化，并且有更多裂解的 caspase-3 阳性细胞，表明细胞凋亡增加。此外，Roc 有效地抑制了骨肉瘤、尤文肉瘤和横纹肌肉瘤细胞以及患者来源的异种移植物的生长。Roc 和 DDR 处理的肉瘤细胞均显示多种致癌激酶水平降低，包括胰岛素样生长因子 1 受体。DDR 和 Roc 更有利的药物样特性以及 Roc 的有效抗肿瘤活性表明，这些罗卡格酰胺可以成为 MPNST 和其他肉瘤的可行治疗方法。