Oncotarget

Research Papers:

Novel Src/Abl tyrosine kinase inhibitor bosutinib suppresses neuroblastoma growth via inhibiting Src/Abl signaling

Shayahati Bieerkehazhi, Zhenghu Chen, Yanling Zhao, Yang Yu, Huiyuan Zhang, Sanjeev A. Vasudevan, Sarah E. Woodfield, Ling Tao, Joanna S. Yi, Jodi A. Muscal, Jonathan C. Pang, Shan Guan, Hong Zhang, Jed G. Nuchtern, Hui Li, Huiwu Li _ and Jianhua Yang

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Oncotarget. 2017; 8:1469-1480. https://doi.org/10.18632/oncotarget.13643

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Abstract

Shayahati Bieerkehazhi1,2,*, Zhenghu Chen3,4,*, Yanling Zhao4, Yang Yu4, Huiyuan Zhang4, Sanjeev A. Vasudevan5, Sarah E. Woodfield5, Ling Tao4, Joanna S. Yi4, Jodi A. Muscal4, Jonathan C. Pang4,6, Shan Guan4, Hong Zhang2, Jed G. Nuchtern5, Hui Li7, Huiwu Li8, Jianhua Yang4

1Department of Labour Hygiene and Sanitary Science, College of Public Health, Xinjiang Medical University, Urumqi, Xinjiang 830011, P.R. China

2Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

3Department of Ophthalmology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P. R. China

4Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA

5Division of Pediatric Surgery, Texas Children’s Hospital Department of Surgery, Michael E. DeBakey Department of Surgery, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA

6Department of Biosciences, Weiss School of Natural Sciences, Rice University, Houston, Texas 77005, USA

7Central Laboratory of Xinjiang Medical University, Urumqi, Xinjiang 830011, P.R. China

8Cancer Prevention and Research Institute, The Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830011, P.R. China

*These authors have contributed equally to this work and should be considered co-first authors

Correspondence to:

Huiwu Li, email: [email protected]

Jianhua Yang, email: [email protected]

Keywords: neuroblastoma, bosutinib, SKI-606, Bosulif, chemotherapy

Received: October 29, 2016     Accepted: November 12, 2016     Published: November 26, 2016

ABSTRACT

Neuroblastoma (NB) is the most common extracranial solid tumor in children. Aberrant activation of the non-receptor tyrosine kinases Src and c-Abl contributes to the progression of NB. Thus, targeting these kinases could be a promising strategy for NB therapy. In this paper, we report that the potent dual Src/Abl inhibitor bosutinib exerts anti-tumor effects on NB. Bosutinib inhibited NB cell proliferation in a dose-dependent manner and suppressed colony formation ability of NB cells. Mechanistically, bosutinib effectively decreased the activity of Src/Abl and PI3K/AKT/mTOR, MAPK/ERK, and JAK/STAT3 signaling pathways. In addition, bosutinib enhanced doxorubicin (Dox)- and etoposide (VP-16)-induced cytotoxicity in NB cells. Furthermore, bosutinib demonstrated anti-tumor efficacy in an orthotopic xenograft NB mouse model in a similar mechanism as of that in vitro. In summary, our results reveal that Src and c-Abl are potential therapeutic targets in NB and that the novel Src/Abl inhibitor bosutinib alone or in combination with other chemotherapeutic agents may be a valuable therapeutic option for NB patients.


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