PT  - JOURNAL ARTICLE
AU  - Esther P. Jane
AU  - Daniel R. Premkumar
AU  - Steven O. Addo-Yobo
AU  - Ian F. Pollack
TI  - Abrogation of Mitogen-Activated Protein Kinase and Akt Signaling by Vandetanib Synergistically Potentiates Histone Deacetylase Inhibitor-Induced Apoptosis in Human Glioma Cells
AID  - 10.1124/jpet.109.155705
DP  - 2009 Oct 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 327--337
VI  - 331
IP  - 1
4099  - http://jpet.aspetjournals.org/content/331/1/327.short
4100  - http://jpet.aspetjournals.org/content/331/1/327.full
SO  - J Pharmacol Exp Ther2009 Oct 01; 331
AB  - Vandetanib is a multitargeted tyrosine kinase inhibitor. Our initial studies demonstrated that this agent blocks vascular endothelial growth factor receptor, epidermal growth factor receptor, and platelet-derived growth factor receptor phosphorylation and mitogen-activated protein kinase (MAPK)-mediated signaling in glioma cell lines in a dose-dependent manner. Despite these effects, we observed that vandetanib had little effect on apoptosis induction at clinically achievable concentrations. Because histone deacetylase inhibitors (HDACIs) have been suggested to regulate signaling protein transcription and downstream interactions via modulation of protein chaperone function through the 90-kDa heat shock protein, we investigated whether combining vandetanib with an HDACI could synergistically potentiate signaling pathway inhibition and apoptosis induction in a panel of malignant human glioma cell lines. Proliferation assays, apoptosis induction studies, and Western immunoblot analysis were conducted in cells treated with vandetanib and HDACIs as single agents or in combination. Vandetanib and suberoylanalide hydroxamic acid reduced proliferation in all cell lines when used as single agents, and the combination produced marked potentiation of growth inhibition as assessed by combinatorial methods. These effects were paralleled by potentiation of Akt signaling inhibition and apoptosis induction. Our results indicate that inhibition of histone deacetylation enhances the antiproliferative effect of vandetanib in malignant human glioma cell lines by enhancing inhibition of MAPK, Akt, and other downstream effectors that may have application in combinatorial therapeutics for these tumors. © 2009 by The American Society for Pharmacology and Experimental Therapeutics