Abstract
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.
Highlights
Glioblastoma multiforme, one of several kinds of gliomas, is a cancer of astrocytes in the brain and the spinal cord, and is the most common and malignant form of cancer of the central nervous system (CNS) [1]
Activation of ionotropic glutamate receptors, that of the AMPA receptors plays a crucial role in growth and migration of glioblastoma cells [13]
We report in the present study that a combination of LY341495, a selective blocker of mGluR2/3, and Iressa, an epidermal growth factor receptor (EGFR) blocker, work most efficiently to inhibit both proliferation and migration of U87 cells and induced maximum apoptosis in the U87 cells
Summary
Glioblastoma multiforme, one of several kinds of gliomas, is a cancer of astrocytes in the brain and the spinal cord, and is the most common and malignant form of cancer of the central nervous system (CNS) [1]. Glutamate levels in U87 cells culture media were high due to its secretion [9] Glutamate activates both fast-acting ionotropic and slow-acting metabotropic glutamate receptors in glial cells and is an important key regulator of invasive growth of glioblastoma [10]. The presence of excessive glutamate promotes invasive growth of glioblastoma cells and kills surrounding neurons due to glutamate neurotoxicity [7,12]. Glioma cells lacking GluR2 showed enhanced migration and, importantly, blocking of Ca2+ influx via AMPA receptor antagonist, NBQX, inhibited growth and induced apoptosis [13,18]. Unedited GluR2 in neurons promotes excitotoxic death when exposed to high glutamate levels via Ca2+ influx and enhanced trafficking of the Ca2+- permeable AMPA receptors [20].
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