Abstract
BackgroundGlioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. Ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, is a novel anticancer drug used for treating several types of cancers. In this study, we aimed to determine the role of ibrutinib on GBM.MethodsCell proliferation was determined by using cell viability, colony formation, and 5-ethynyl-2′-deoxyuridine (EdU) assays. Cell cycle and cell apoptosis were analyzed by flow cytometry. Cell migratory ability was evaluated by wound healing assays and trans-well migration assays. ATG7 expression was knocked-down by transfection with Atg7-specific small interfering RNA. Overexpression of active Akt protein was achieved by transfecting the cells with a plasmid expressing constitutively active Akt (CA-Akt). Transmission electron microscopy was performed to examine the formation of autophagosomes in cells. Immunofluorescence and western blot analyses were used to analyze protein expression. Tumor xenografts in nude mice and immunohistochemistry were performed to evaluate the effect of ibrutinib on tumor growth in vivo.ResultsIbrutinib inhibited cellular proliferation and migration, and induced apoptosis and autophagy in LN229 and U87 cells. Overexpression of the active Akt protein decreased ibrutinib-induced autophagy, while inhibiting Akt by LY294002 treatment enhanced ibrutinib-induced autophagy. Specific inhibition of autophagy by 3-methyladenine (3MA) or Atg7 targeting with small interfering RNA (si-Atg7) enhanced the anti-GBM effect of ibrutinib in vitro and in vivo.ConclusionsOur results indicate that ibrutinib exerts a profound antitumor effect and induces autophagy through Akt/mTOR signaling pathway in GBM cells. Autophagy inhibition promotes the antitumor activity of ibrutinib in GBM. Our findings provide important insights into the action of an anticancer agent combining with autophagy inhibitor for malignant glioma.
Highlights
Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults
We noted that the expression of Bruton’s tyrosine kinase (BTK) in GBM tissues deposited in the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GSE7696, GSE16011) is up-regulated (Additional file 1: Figure S1)
The results indicated that ibrutinib decreased GBM cell viability in a dose-dependent manner
Summary
A Bruton’s tyrosine kinase (BTK) inhibitor, is a novel anticancer drug used for treating several types of cancers. Wang et al Journal of Experimental & Clinical Cancer Research (2017) 36:96 residue adjacent to an ATP-binding site; this residue is critical for covalent inhibition of these enzymes by tyrosine kinase inhibitors [5, 6]. Formerly known as PCI-32765, selectively and irreversibly inhibits BTK, and is administered once-daily to prevent B-cell differentiation, proliferation, and survival [7]. Ibrutinib has been used as a novel anticancer drug for several other types of cancers, such as human ovarian, breast, and lung cancer, and gastric carcinoma, and glioma [11,12,13,14]. Ibrutinib may function as a novel small molecule inhibitor in GBM patients
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callMore From: Journal of Experimental & Clinical Cancer Research
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
