Synergistic inhibition of survival, proliferation, and migration of U87 cells with a combination of LY341495 and Iressa

• Published in: PloS one Vol. 8; no. 5; p. e64588
• Main Authors: Yelskaya, Zarina, Carrillo, Vangie, Dubisz, Ewa, Gulzar, Hira, Morgan, Devon, Mahajan, Shahana S
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 27.05.2013; Public Library of Science (PLoS)
• Subjects: Amino Acids - pharmacology; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Biology; Breast cancer; Cancer therapies; Cell adhesion & migration; Cell growth; Cell Line, Tumor; Cell migration; Cell Movement - drug effects; Cell proliferation; Cell Proliferation - drug effects; Cell survival; Cell Survival - drug effects; Combinatorial analysis; Dose-Response Relationship, Drug; Drug Synergism; Drugs; Epidermal growth factor; Epidermal growth factor receptors; Glioblastoma; Glioblastoma - metabolism; Glutamic Acid - metabolism; Glutamic Acid - pharmacology; Glutamic acid receptors (metabotropic); Health sciences; Humans; Inhibitors; Kinases; Medical prognosis; Medicine; Phosphorylation; Propionic acid; Proteins; Quinazolines - pharmacology; Riluzole - pharmacology; Rodents; Synergistic effect; Xanthenes - pharmacology; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; New York; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0064588

Glioblastomas exploit various molecular pathways to promote glutamate- dependent growth by activating the AMPA (2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propanoic acid) receptor, the group II metabotropic glutamate receptor, mGluR, and the epidermal growth factor receptor, EGFR. We hypothesized that targeting more than one of these pathways would be more effective in inhibiting glutamate-dependent growth. Using a model of U87 cell line, we show that blocking glutamate release by Riluzole inhibits cell proliferation. Glutamate-dependent growth is effectively inhibited by a combination of Iressa, an inhibitor of EGFR activation and LY341495, a group II mGluR inhibitor. Treatment of U87 cells with a combination of Iressa and LY341495 inhibits proliferation as indicated by Ki-67 staining, induces apoptosis and inhibits migration of U87 cells more effectively than the treatment by Iressa or LY341495 alone. These results demonstrate that a combinatorial therapy with Iressa and LY341495 is more effective due to synergistic effects of these drugs in inhibiting the growth of glioblastoma.