Levetiracetam enhances p53-mediated MGMT inhibition and sensitizes glioblastoma cells to temozolomide.
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 of MGMT expression. 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.
Bobustuc
George C
GC
Cancer Research Institute, M. D. Anderson Cancer Center Orlando, Orlando, Florida 32806, USA. george.bobustuc@orlandohealth.com
Baker
Cheryl H
CH
Limaye
Arati
A
Jenkins
Wayne D
WD
Pearl
Gary
G
Avgeropoulos
Nicholas G
NG
Konduri
Santhi D
SD
D000927:Anticonvulsants / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D015254:DNA Modification Methylases / Q000378:metabolism*; D045643:DNA Repair Enzymes / Q000378:metabolism*; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects*; D005909:Glioblastoma / Q000378:metabolism*; D006801:Humans; D000077287:Levetiracetam; D010889:Piracetam / Q000031:analogs & derivatives* / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077204:Temozolomide; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D000927:Anticonvulsants; D000970:Antineoplastic Agents; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D000077287:Levetiracetam; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide; D010889:Piracetam