Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China.
Thorac Cancer. 2019 Apr;10(4):642-658. doi: 10.1111/1759-7714.12976. Epub 2019 Feb 18.
Small-cell lung cancer (SCLC), a malignant tumor, is usually widely metastatic when diagnosed. The lack of important therapeutic clinical advances makes it difficult to treat. Previous studies showed that Adjudin had anticancer effects in many other human cancers, and it was synergetic with cisplatin in non-small cell lung cancer. However, the mechanism on SCLC was unclear.
We investigated the potential mechanism and effect of Adjudin on SCLC both in vitro and in vivo.
An SCLC xenograft model showed that Adjudin inhibited tumor growth and was significantly synergetic with paclitaxel (in vitro as well). Cell Counting Kit-8 assays, flow cytometric analysis and western blotting showed that Adjudin effectively suppressed SCLC cell proliferation by inducing S phase arrest and caspase-dependent apoptosis. Moreover, Transwell and scratch assays showed that Adjudin also effectively inhibited migration and invasion. Furthermore, Adjudin activated the sirtuin 3 (SIRT3)-Forkhead box O3a (FOXO3a) pathway. Downregulating SIRT3 or FOXO3a significantly attenuated Adjudin-induced anticancer effects. Furthermore, higher expression of SIRT3 and FOXO3a were positively correlated, and both were associated with longer survival in lung cancer patients.
Overall, the present study is the first to show that Adjudin synergizes with paclitaxel and inhibits cell growth and metastasis by regulating the SIRT3-FOXO3a axis in SCLC; thus, Adjudin has great potential to be an anticancer agent.
小细胞肺癌（SCLC）是一种恶性肿瘤，通常在诊断时已广泛转移。缺乏重要的治疗临床进展使得其难以治疗。先前的研究表明，Adjudin 在许多其他人类癌症中具有抗癌作用，并且与非小细胞肺癌中的顺铂具有协同作用。然而，其在 SCLC 中的机制尚不清楚。
我们在体外和体内研究了 Adjudin 对 SCLC 的潜在作用机制。
SCLC 异种移植模型表明，Adjudin 抑制肿瘤生长，与紫杉醇（体外也是如此）具有显著协同作用。细胞计数试剂盒-8 测定、流式细胞术分析和 Western blot 表明，Adjudin 通过诱导 S 期阻滞和 caspase 依赖性细胞凋亡有效抑制 SCLC 细胞增殖。此外，Transwell 和划痕实验表明，Adjudin 还能有效抑制迁移和侵袭。此外，Adjudin 激活了沉默信息调节因子 3（SIRT3）-叉头框蛋白 O3a（FOXO3a）通路。下调 SIRT3 或 FOXO3a 可显著减弱 Adjudin 诱导的抗癌作用。此外，SIRT3 和 FOXO3a 的高表达呈正相关，两者均与肺癌患者的生存时间延长相关。
总的来说，本研究首次表明，Adjudin 通过调节 SCLC 中的 SIRT3-FOXO3a 轴与紫杉醇协同作用并抑制细胞生长和转移；因此，Adjudin 具有成为抗癌药物的巨大潜力。
