Novel multiple tyrosine kinase inhibitor ponatinib inhibits bFGF-activated signaling in neuroblastoma cells and suppresses neuroblastoma growth in vivo
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Haoyu Li1,2,4,*, Yongfeng Wang3,4,*, Zhenghu Chen4,5,*, Jiaxiong Lu4, Jessie Pan4, Yang Yu4, Yanling Zhao4, Huiyuan Zhang4, Ting Hu1,2,4, Qing Liu1,2, Jianhua Yang4
1Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha 410008, China
2The Institute of Skull Base Surgery and Neurooncology at Hunan Province, 410008, China
3Department of Microbiology, Peking University Health Science Center, Beijing 100191, China
4Texas Children’s Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA
5Department of Ophthalmology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, P. R. China
*These authors contributed equally to this work and should be considered as co-first authors
Qing Liu, email: firstname.lastname@example.org
Jianhua Yang, email: email@example.com
Keywords: neuroblastoma, ponatinib, FGFR1, apoptosis, chemoresistance
Received: June 13, 2016 Accepted: August 15, 2016 Published: August 24, 2016
Neuroblastoma (NB) is one of the most common pediatric malignancies in children. Abnormal activation of receptor tyrosine kinases contributes to the pathological development of NB. Therefore, targeting tyrosine kinase receptors to cure NB is a promising strategy. Here, we report that a multi-targeted tyrosine kinase inhibitor ponatinib inhibited NB cell proliferation and induced NB cell apoptosis in a dose-dependent manner. In addition, ponatinib suppressed the colony formation ability of NB cells. Mechanistically, ponatinib effectively inhibited the FGFR1-activated signaling pathway. Ponatinib also enhanced the cytotoxic effects of doxorubicin on NB cells. Furthermore, ponatinib demonstrated anti-tumor efficacy in vivo by inhibiting tumor growth in an orthotopic xenograft NB mouse model. In summary, our results showed that ponatinib inhibited NB growth both in vitro and in vivo.
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