Department of Health Sciences, Hunter College, City University of New York, New York, New York, United States of America.
PLoS One. 2013 May 27;8(5):e64588. doi: 10.1371/journal.pone.0064588. Print 2013.
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.
胶质母细胞瘤通过激活 AMPA（2-氨基-3-（3-羟基-5-甲基异恶唑-4-基）丙酸）受体、代谢型谷氨酸受体 2（mGluR2）和表皮生长因子受体（EGFR）等多种分子途径促进谷氨酸依赖性生长。我们假设靶向这些途径中的多个途径将更有效地抑制谷氨酸依赖性生长。我们使用 U87 细胞系模型表明，通过利鲁唑阻断谷氨酸释放可抑制细胞增殖。通过伊瑞沙（一种 EGFR 激活抑制剂）和 LY341495（一种 mGluR2 抑制剂）联合使用可有效抑制谷氨酸依赖性生长。与伊瑞沙或 LY341495 单独治疗相比，用伊瑞沙和 LY341495 的联合治疗通过 Ki-67 染色抑制 U87 细胞的增殖，诱导细胞凋亡并抑制 U87 细胞的迁移，效果更显著。这些结果表明，由于这些药物在抑制胶质母细胞瘤生长方面具有协同作用，因此联合使用伊瑞沙和 LY341495 的联合疗法更有效。
