Levetiracetam enhances p53-mediated MGMT inhibition and sensitizes glioblastoma cells to temozolomide

    Authors

    G. C. Bobustuc; C. H. Baker; A. Limaye; W. D. Jenkins; G. Pearl; N. G. Avgeropoulos;S. D. Konduri

    Comments

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    Abbreviated Journal Title

    Neuro-Oncology

    Keywords

    gliomas; levetiracetam; MGMT; mSin3A/HDAC1; p53; temozolomide; O-6-METHYLGUANINE-DNA METHYLTRANSFERASE GENE; DNA CROSS-LINKING; HUMAN-TUMOR-CELLS; O-6-ALKYLGUANINE-DNA ALKYLTRANSFERASE; TRANSCRIPTIONAL REPRESSION; ANTIEPILEPTIC DRUGS; ALKYLATING-AGENTS; CLINICAL-RESPONSE; REPAIR; P53; Oncology; Clinical Neurology

    Abstract

    Antiepileptic drugs (AEDs) are frequently used to treat seizures in glioma patients. AEDs may have an unrecognized impact in modulating O 6 -methylguanine-DNA methyltransferase (MGMT), a DNA repair protein that has an important role in tumor cell resistance to alkylating agents. We report that levetiracetam (LEV) is the most potent MGMT inhibitor among several AEDs with diverse MGMT regulatory actions. In vitro, when used at concentrations within the human therapeutic range for seizure prophylaxis, LEV decreases MGMT protein and mRNA expression levels. Chromatin immunoprecipitation analysis reveals that LEV enhances p53 binding on the MGMT promoter by recruiting the mSin3A/ histone deacetylase 1 (HDAC1) corepressor complex. However, LEV does not exert any MGMT inhibitory activity when the expression of either p53, mSin3A, or HDAC1 is abrogated. LEV inhibits malignant glioma cell proliferation and increases glioma cell sensitivity to the monofunctional alkylating agent temozolomide. In 4 newly diagnosed patients who had 2 craniotomies 7-14 days apart, prior to the initiation of any tumor-specific treatment, samples obtained before and after LEV treatment showed the inhibition ofMGMTexpression. Our results suggest that the choice of AED in patients with malignant gliomas may have an unrecognized impact in clinical practice and research trial design.

    Journal Title

    Neuro-Oncology

    Volume

    12

    Issue/Number

    9

    Publication Date

    1-1-2010

    Document Type

    Article

    Language

    English

    First Page

    917

    Last Page

    927

    WOS Identifier

    WOS:000281184200004

    ISSN

    1522-8517

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