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.
Highlights
Neuroblastoma (NB), the most common pediatric extracranial solid tumor [1], is responsible for over 15% of childhood cancer-related deaths [2, 3]
Other studies have shown that Src/Abl tyrosine kinase inhibitor dasatinib exerts anti-tumor effects in both NB cells and an orthotopic mouse model [19]
We report that the novel dual Src/Abl inhibitor bosutinib inhibited NB cell proliferation in a time dependent manner and impaired anchorage-independent growth of NB cells
Summary
Neuroblastoma (NB), the most common pediatric extracranial solid tumor [1], is responsible for over 15% of childhood cancer-related deaths [2, 3]. Src is a member of the non-receptor tyrosine kinase family and it participates in intracellular signaling www.impactjournals.com/oncotarget pathways and has been frequently associated with cell migration, proliferation, and apoptosis [7,8,9]. Multiple studies have shown that abnormally activated Src is frequently associated with the malignancy of a variety of human cancer types [10, 11]. Overexpression of the Src kinase in advanced NB patients has been associated with poor outcomes [18], and inhibition of Src tyrosine kinase activity results in decreased cell proliferation and apoptosis induction in NB cells [19,20,21]. Targeting Src tyrosine kinase to cure NB is a feasible solution in NB therapy
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