Research Papers:

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

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

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Oncotarget. 2017; 8:87209-87220. https://doi.org/10.18632/oncotarget.20257

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Yuqiong Xie1,*, Chunchun Li1,*, Yali Huang2, Zhenyu Jia3 and Jiang Cao1

1Clinical Research Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China

2Institute of Hygiene, Zhejiang Academy of Medical Sciences, Hangzhou 310013, China

3Institute of Occupational Diseases, Zhejiang Academy of Medical Sciences, Hangzhou 310013, China

*These authors have contributed equally to this work

Correspondence to:

Jiang Cao, email: [email protected]

Zhenyu Jia, email: [email protected]

Keywords: multikinase inhibitor, targeted therapy, cancer, autophagy, apoptosis

Received: May 19, 2017     Accepted: July 13, 2017     Published: August 14, 2017


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.

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