A novel multikinase inhibitor R8 exhibits potent inhibition on cancer cells through both apoptosis and autophagic cell death.

Yuqiong Xie,Jiang Cao,Zhenyu Jia,Yali Huang,Chunchun Li

doi:10.18632/oncotarget.20257

Abstract

Chemotherapy is an important treatment for cancer patients, especially for those with unresectable lesions. Targeted therapy of cancer by specific inhibition of aberrant tyrosine kinase activities in cancer cells with chemically synthesized tyrosine kinase inhibitors (TKIs), shows better responses while less side effects than traditional chemotherapeutic drugs. It is common that cancer cells often exhibit deregulation of several tyrosine kinases simultaneously, multikinase TKIs (MKIs) therefore have greater advantages over single-target TKIs. Currently more MKIs are under developing for better efficacy for different types of cancer. In the present work, we evaluated the in vitro therapeutic potential of a novel MKI, namely R8, with comparison to the clinically available MKI Sunitinib. Results showed that R8 has stronger inhibition on six different types of cancer cell lines with lower IC50 than Sunitinib does. Cell cycle analysis showed that R8 induced significant G0/G1 arrest phase of lung cancer A549 and NCI-H226 cells. The inhibition was also confirmed by colony formation and migration assays in both lung cancer cell lines in a dose-dependent manner. R8 could significantly inhibit the phosphorylation of multiple receptor tyrosine kinases (RTKs) included PDGFRβ, VEGFR2, EGFR and C-Kit, leading to the down-regulation of PI3K-Akt-mTOR signaling. Further analysis revealed that R8 treatment induced more significant apoptosis than Sunitinib did, which might be the consequence of the autophagic cell death. In conclusion, this work suggested R8 to be a promising novel anticancer MKI, and provided the basis for further in vivo investigation on its potential in treatment of lung cancer.

Highlights

Cancer is one of the leading causes of death worldwide, with an estimated 14.1 million new cases and 8.2 million deaths occurred in 2012 worldwide [1]
It is common that cancer cells often exhibit simultaneous deregulation of several tyrosine kinases, such as epithelial growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor (VEGFR), etc., which lead to the malignant characteristics www.impactjournals.com/oncotarget of tumor such as uncontrolled proliferation, invasiveness and angiogenesis, multi-target tyrosine kinase inhibitor (TKI) have great advantages over single-target TKIs [2]
We further focused on the mechanism for its inhibition on lung cancer cells which showed distinct characteristics compared to Sunitinib, a clinically available multi-target tyrosine kinase inhibitor (MKI) which has been investigated extensively in many types of cancer including lung cancer, either used alone or in combination with other therapeutics [9,10,11]

Summary

Introduction

Cancer is one of the leading causes of death worldwide, with an estimated 14.1 million new cases and 8.2 million deaths occurred in 2012 worldwide [1]. Many TKIs/MKIs have been widely used clinically in the treatment of various types of cancer, they do not always give satisfactory outcomes, even for individuals with definite hyper-activated target kinases. Primary resistance and acquired resistance are commonly observed because of the fact that, each type of cancer or even each individual cancer cell may show different aberrantly activated tyrosine kinases due to heterogenicity during the development and progression of the disease, and the TKIs/MKIs may have different binding and inhibition selectivities on different kinases (and even same kinase with different mutations) [3,4,5]. More multi-target TKIs are developed or under developing for better efficacies on different individuals and to overcome the primary or acquired resistance [6,7,8]

Methods

Results

Conclusion