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Research ArticleCELLULAR AND MOLECULAR

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

Esther P. Jane, Daniel R. Premkumar and Ian F. Pollack
Journal of Pharmacology and Experimental Therapeutics December 2006, 319 (3) 1070-1080; DOI: https://doi.org/10.1124/jpet.106.108621
Esther P. Jane
Department of Neurosurgery, University of Pittsburgh School of Medicine, University of Pittsburgh Cancer Institute Brain Tumor Center, Pittsburgh, Pennsylvania
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Daniel R. Premkumar
Department of Neurosurgery, University of Pittsburgh School of Medicine, University of Pittsburgh Cancer Institute Brain Tumor Center, Pittsburgh, Pennsylvania
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Ian F. Pollack
Department of Neurosurgery, University of Pittsburgh School of Medicine, University of Pittsburgh Cancer Institute Brain Tumor Center, Pittsburgh, Pennsylvania
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Abstract

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-δ 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-δ 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.

  • Received May 29, 2006.
  • Accepted September 5, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 384 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 384, Issue 2
1 Feb 2023
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Research ArticleCELLULAR AND MOLECULAR

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

Esther P. Jane, Daniel R. Premkumar and Ian F. Pollack
Journal of Pharmacology and Experimental Therapeutics December 1, 2006, 319 (3) 1070-1080; DOI: https://doi.org/10.1124/jpet.106.108621

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Research ArticleCELLULAR AND MOLECULAR

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

Esther P. Jane, Daniel R. Premkumar and Ian F. Pollack
Journal of Pharmacology and Experimental Therapeutics December 1, 2006, 319 (3) 1070-1080; DOI: https://doi.org/10.1124/jpet.106.108621
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