Norditerpenoids and dinorditerpenoids represent diterpenoids widely distributed in the genus Podocarpus with notable chemical structures and biological activities. We previously reported that nagilactone E (NLE), a dinorditerpenoid isolated from Podocarpus nagi, possessed anticancer effects against lung cancer cells in vitro. In this study we investigated the in vivo effect of NLE against lung cancer as well as the underlying mechanisms. We administered NLE (10 mg·kg⁻¹·d⁻¹, ip) to CB-17/SCID mice bearing human lung cancer cell line A549 xenograft for 3 weeks. We found that NLE administration significantly suppressed the tumor growth without obvious adverse effects. Thereafter, RNA sequencing (RNA-seq) analysis was performed to study the mechanisms of NLE. The effects of NLE on A549 cells have been illustrated by GO and pathway enrichment analyses. CMap dataset analysis supported NLE to be a potential protein synthesis inhibitor. The inhibitory effect of NLE on synthesis of total de novo protein was confirmed in Click-iT assay. Using the pcDNA3-RLUC-POLIRES-FLUC luciferase assay we further demonstrated that NLE inhibited both cap-dependent and cap-independent translation. Finally, molecular docking revealed the low-energy binding conformations of NLE and its potential target RIOK2. In conclusion, NLE is a protein synthesis inhibitor with anticancer activity.

去甲二萜和二去甲二萜代表了广泛分布于罗汉松属中的二萜，具有显着的化学结构和生物活性。我们之前曾报道过，从罗汉松中分离出来的二去甲二萜类药物 nagilactone E (NLE)在体外对肺癌细胞具有抗癌作用。在这项研究中，我们研究了 NLE 对肺癌的体内作用以及潜在的机制。我们给予 NLE (10 mg·kg ^-1 ·d ^-1, ip) 对带有人肺癌细胞系 A549 异种移植物的 CB-17/SCID 小鼠进行 3 周。我们发现 NLE 给药显着抑制了肿瘤生长而没有明显的副作用。此后，进行了 RNA 测序 (RNA-seq) 分析以研究 NLE 的机制。NLE 对 A549 细胞的影响已通过 GO 和通路富集分析进行了说明。CMap 数据集分析支持 NLE 成为潜在的蛋白质合成抑制剂。在 Click-iT 测定中证实了 NLE 对总从头蛋白合成的抑制作用。使用 pcDNA3-RLUC-POLIRES-FLUC 荧光素酶测定，我们进一步证明 NLE 抑制帽依赖性和帽非依赖性翻译。最后，分子对接揭示了 NLE 的低能结合构象及其潜在靶标 RIOK2。综上所述，