QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.106.108621v1 319/3/1070    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jane, E. P. Articles by Pollack, I. F. Search for Related Content PubMed PubMed Citation Articles by Jane, E. P. Articles by Pollack, I. F.

CELLULAR AND MOLECULAR

Coadministration of Sorafenib with Rottlerin Potently Inhibits Cell Proliferation and Migration in Human Malignant Glioma Cells

Department of Neurosurgery, University of Pittsburgh School of Medicine, University of Pittsburgh Cancer Institute Brain Tumor Center, Pittsburgh, Pennsylvania

Mitogen-activated protein kinase (MAPK) and protein kinase C (PKC) are activated in the majority of gliomas and contribute to tumor cell growth and survival. Sorafenib (Bay43-9006; Nexavar) is a dual-action Raf and vascular endothelial growth factor receptor inhibitor that blocks receptor phosphorylation and MAPK-mediated signaling and inhibits growth in a number of tumor types. Because our initial studies of this agent in a series of glioma cell lines showed only partial growth inhibition at clinically achievable concentrations, we questioned whether inhibition of PKC signaling using the PKC- inhibitor rottlerin might potentiate therapeutic efficacy. Proliferation assays, apoptosis induction studies, and Western immunoblot analysis were conducted in cells treated with sorafenib and rottlerin as single agents or in combination. Sorafenib and rottlerin reduced proliferation in all cell lines when used as single agents, and the combination produced marked potentiation of growth inhibition. Flow-cytometric measurements of cells stained with Annexin V-propidium iodide and immunocytochemical assessment of cytochrome c and apoptosis-inducing factor release demonstrated that addition of rottlerin resulted in significantly higher levels of apoptosis than sorafenib alone. In addition, the combination of sorafenib and rottlerin reduced or completely inhibited the phosphorylation of extracellular signal-regulated kinase and Akt and down-regulated cell cycle regulatory proteins such as cyclin-D1, cyclin-D3, cyclin-dependent kinase (cdk)4, and cdk6 in a dose- and time-dependent manner. Our results clearly indicate that inhibition of PKC- signaling enhances the antiproliferative effect of sorafenib in malignant human glioma cell lines and support the examination of combinations of signaling inhibitors in these tumors.

Address correspondence to: Dr. Ian F. Pollack, Department of Neurosurgery, Children's Hospital of Pittsburgh, 3705 Fifth Ave., Pittsburgh, PA 15213. E-mail: ian.pollack{at}chp.edu

This article has been cited by other articles:

				M. A. Tran, C. D. Smith, M. Kester, and G. P. Robertson Combining Nanoliposomal Ceramide with Sorafenib Synergistically Inhibits Melanoma and Breast Cancer Cell Survival to Decrease Tumor Development Clin. Cancer Res., June 1, 2008; 14(11): 3571 - 3581. [Abstract] [Full Text] [PDF]

				S. V. Madhunapantula and G. P. Robertson Is B-Raf a Good Therapeutic Target for Melanoma and Other Malignancies? Cancer Res., January 1, 2008; 68(1): 5 - 8. [Abstract] [Full Text] [PDF]

				J. P. Plastaras, S.-H. Kim, Y. Y. Liu, D. T. Dicker, J. F. Dorsey, J. McDonough, G. Cerniglia, R. R. Rajendran, A. Gupta, A. K. Rustgi, et al. Cell Cycle Dependent and Schedule-Dependent Antitumor Effects of Sorafenib Combined with Radiation Cancer Res., October 1, 2007; 67(19): 9443 - 9454. [Abstract] [Full Text] [PDF]

				R. R. Rosato, J. A. Almenara, S. Coe, and S. Grant The Multikinase Inhibitor Sorafenib Potentiates TRAIL Lethality in Human Leukemia Cells in Association with Mcl-1 and cFLIPL Down-regulation Cancer Res., October 1, 2007; 67(19): 9490 - 9500. [Abstract] [Full Text] [PDF]