Key Laboratory of Computational Chemistry Based Natural Antitumor Drug Research & Development, Liaoning Province, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, PR China.
Key Laboratory of Computational Chemistry Based Natural Antitumor Drug Research & Development, Liaoning Province, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, PR China.
Eur J Pharmacol. 2022 Jun 15;925:174989. doi: 10.1016/j.ejphar.2022.174989. Epub 2022 Apr 28.
Scabertopin (SCP), an abundant germacrane-type sesquiterpene lactone (SLC) isolated from Elephantopus scaber, was selected as a reference compound for modification and evaluation as anticancer agents for non-small cell lung cancer (NSCLC) treatment. All derivatives (SCP-1-SCP-13) except for SCP-3 showed potential inhibitory effect (IC 5.2-9.7 μM) against A549 cells. The most promising compound SCP-7 also showed good cytotoxic activity against another two NSCLC cell lines (H1299 and H460), with IC value of 4.4 and 8.9 μM, respectively. Furthermore, SCP-7 could induce apoptotic cell death that was associated with the increased reactive oxygen species (ROS) generation, the loss of mitochondrial membrane potential, Bcl-2 family proteins modulation, caspases-3 and PARP cleavage. In addition, SCP-7 also inhibited cell growth by increasing Bax expression and reducing the Ki-67 positive cells in vivo, but there were no obvious toxic and side effects on internal organs. Mechanistically, PharmMapper, molecular docking and Western blot analysis revealed that SCP-7 might interact with the epidermal growth factor receptor (EGFR) and inhibit its expression in lung cancer cells. Together, above results suggest further effective application of SCP-7 as a potential anti-tumor agent in the treatment of NSCLC.
Scabertopin (SCP)，一种从 Elephantopus scaber 中分离得到的丰富的倍半萜内酯 (SLC)，被选为用于修饰和评估作为非小细胞肺癌 (NSCLC) 治疗的抗癌剂的参考化合物。除 SCP-3 外，所有衍生物 (SCP-1-SCP-13) 均显示出对 A549 细胞的潜在抑制作用 (IC 50.2-9.7 μM)。最有前途的化合物 SCP-7 对另外两种 NSCLC 细胞系 (H1299 和 H460) 也表现出良好的细胞毒性活性，IC 值分别为 4.4 和 8.9 μM。此外，SCP-7 可以诱导与活性氧 (ROS) 生成增加、线粒体膜电位丧失、Bcl-2 家族蛋白调节、caspases-3 和 PARP 切割相关的凋亡细胞死亡。此外，SCP-7 还通过增加 Bax 表达和减少体内 Ki-67 阳性细胞来抑制细胞生长，但对内脏器官没有明显的毒性和副作用。从机制上讲，PharmMapper、分子对接和 Western blot 分析表明，SCP-7 可能与表皮生长因子受体 (EGFR) 相互作用并抑制其在肺癌细胞中的表达。总之，上述结果表明 SCP-7 作为 NSCLC 治疗中潜在的抗肿瘤药物具有进一步的有效应用。
