The multi-targeted tyrosine kinase inhibitor vandetanib plays a bifunctional role in non-small cell lung cancer cells.

Yan Zhou,Hanbing Zou,Longmei Xu,Xiaojing Chen,Ning Cai,Xianming Kong,Peifeng Liu,Yuanliang Zhang

doi:10.1038/srep08629

Abstract

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.

Highlights

The multi-targeted tyrosine kinase inhibitor vandetanib plays a bifunctional role in non-small cell lung cancer cells
Treatment of cells with vandetanib did not affect the mRNA expression of the epithelial-mesenchymal transition (EMT) marker genes relative to control cells (Supplementary Figure S1), suggesting that vandetanib did not induce the mesenchymal-epithelial transition (MET) observed in Calu-6 cells
We found that vandetanib treatment reduced the protein expression levels of both p-extracellular signal-regulated kinase (ERK) and p-Jun NH2 terminal kinase (JNK) in A549 and H1795 cells (Supplement Figure S3A) but did not alter the morphology of these two cell lines (Supplement Figure S3B), suggesting that vandetanib-induced inhibition of p-JNK is a general effect among non-small cell lung cancer (NSCLC) cells

Summary

Introduction

The multi-targeted tyrosine kinase inhibitor vandetanib plays a bifunctional role in non-small cell lung cancer cells. Vandetanib, a multikinase inhibitor, is a target of drug treatments for non-small cell lung cancer (NSCLC). Lung cancer is one of the most common cancers and non-small cell lung cancer (NSCLC) accounts for 80–85% of all lung cancers Effective treatments such as surgery, chemotherapy, and radiotherapy have been greatly improved, the 5-year survival rate for patients is still very low[1], and there is an urgent need for better treatment options. VEGFR is required for tumor angiogenesis[12], and KIF5B-RET translocation occurs in approximately 1–2% of lung adenocarcinoma[13] These data indicate that vandetanib may represent a potential treatment option for NSCLC14,15. Recent studies have shown that autophagy plays a role in tumor cell survival and cell death[19,20,21]

Methods

Results

Conclusion