Zhou Yan, Zhang Yuanliang, Zou Hanbing, Cai Ning, Chen Xiaojing, Xu Longmei, Kong Xianming, Liu Peifeng
Central Laboratory, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai. 200127, People's Republic of China.
Shanghai Institute of Hematology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai. 200025, People's Republic of China.
Sci Rep. 2015 Feb 27;5:8629. doi: 10.1038/srep08629.
Vandetanib, a multikinase inhibitor, is a target of drug treatments for non-small cell lung cancer (NSCLC). However, phase II and III clinical trials have not conclusively demonstrated the curative effects of vandetanib for NSCLC, and the reasons for this are unknown. In the present study, we use the NSCLC cell line Calu-6 as a model to determine the cellular and biological effects of vandetanib. Our results demonstrate that vandetanib impairs Calu-6 cell migration and invasion. We find that vandetanib can directly inhibit RET activity, which influences the Rho-JNK pathway. Overexpression of a constitutively active Rho GTPase antagonizes the inhibitory effects of vandetanib on Calu-6 cells invasion and JNK pathway activation. In addition, vandetanib induces autophagy by increasing the level of reactive oxygen species (ROS) in Calu-6 cells, and blockade of autophagy or ROS effectively enhances the cell death effect of vandetanib. In this study, we find vandetanib is of a double effect in some NSCLC cells, presenting new possibilities for the pharmacological treatment of NSCLC and introducing a novel role for vandetanib in treatment options.
凡德他尼是一种多激酶抑制剂，是非小细胞肺癌（NSCLC）药物治疗的靶点。然而，II期和III期临床试验尚未最终证实凡德他尼对NSCLC的疗效，其原因尚不清楚。在本研究中，我们以NSCLC细胞系Calu-6为模型，确定凡德他尼的细胞和生物学效应。我们的结果表明，凡德他尼会损害Calu-6细胞的迁移和侵袭。我们发现凡德他尼可直接抑制RET活性，这会影响Rho-JNK途径。组成型活性Rho GTP酶的过表达可拮抗凡德他尼对Calu-6细胞侵袭和JNK途径激活的抑制作用。此外，凡德他尼通过增加Calu-6细胞中的活性氧（ROS）水平诱导自噬，而阻断自噬或ROS可有效增强凡德他尼对细胞的杀伤作用。在本研究中我们发现凡德他尼在某些NSCLC细胞中具有双重作用，为NSCLC药物治疗提供了新可能性，并揭示了凡德他尼在治疗选择中的新作用。
