College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea.
CKD Research Institution, Chong Kun Dang Pharmaceutical Corporation, Yongin-si, Gyeonggi-do, 16995, Republic of Korea.
Cancer Chemother Pharmacol. 2020 Apr;85(4):685-697. doi: 10.1007/s00280-020-04043-x. Epub 2020 Mar 11.
CKD-516 (Valecobulin), a vascular-disrupting agent, inhibits microtubule elongation. We evaluated the effect of CKD-516 on lung cancer cells and the underlying molecular mechanisms.
The effects of S516, an active metabolite of CKD-516, were evaluated in HUVECs and three lung cancer cell lines and by a microtubule polymerization assay. Tubulin cross-linking was used to identify the binding site of S516 on tubulin, and Western blotting was performed to identify the intracellular pathways leading to cell death. Subcutaneous lung cancer xenograft models were used to assess the in vivo effect of CKD-516 on tumor growth.
S516 targeted the colchicine binding site on β-tubulin. In lung cancer cells, S516 increased endoplasmic reticulum (ER) stress and induced reactive oxygen species (ROS) generation by mitochondria and the ER. In addition, CKD-516 monotherapy strongly inhibited the growth of lung cancer xenograft tumors and exerted a synergistic effect with carboplatin.
The findings suggest that CKD-516 exerts an anticancer effect in company with inducing ER stress and ROS production via microtubule disruption in lung cancer cells. CKD-516 may thus have therapeutic potential for lung cancer.
CKD-516（伐利科布林）是一种血管破坏剂，可抑制微管的延长。我们评估了 CKD-516 对肺癌细胞的作用及其潜在的分子机制。
在 HUVECs 和三种肺癌细胞系中，通过微管聚合测定法评估 S516（CKD-516 的一种活性代谢物）的作用。用微管交联来鉴定 S516 在微管上的结合位点，并用 Western blot 鉴定导致细胞死亡的细胞内途径。使用皮下肺癌异种移植模型来评估 CKD-516 对肿瘤生长的体内作用。
S516 靶向β-微管上的秋水仙碱结合位点。在肺癌细胞中，S516 通过线粒体和内质网（ER）增加内质网（ER）应激并诱导活性氧（ROS）的产生。此外，CKD-516 单药强烈抑制肺癌异种移植肿瘤的生长，并与卡铂具有协同作用。
这些发现表明，CKD-516 通过破坏微管在肺癌细胞中诱导内质网应激和 ROS 产生，从而发挥抗癌作用。因此，CKD-516 可能对肺癌具有治疗潜力。
