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

Bobustuc, George C.; Baker, Cheryl H.; Limaye, Arati; Jenkins, Wayne D.; Pearl, Gary S.; Avgeropoulos, Nicholas G.; Konduri, Santhi D.

doi:10.1093/neuonc/noq044

Cited by 134 publications

(115 citation statements)

References 25 publications

(33 reference statements)

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“…To date, a number of methods have been described to inhibit MGMT; however, their significance in clinical use for the purpose of overcoming temozolomide resistance is still limited or unknown [3,37,38]. Here, we have shown that the molecular pathway linking MEK to MGMT expression could offer novel and rational targets for MGMT inactivation, specifically MEK (by SL327) and MDM2 (by Nutlin-3).…”

Section: Resultsmentioning

confidence: 87%

MEK-ERK Signaling Dictates DNA-Repair Gene MGMT Expression and Temozolomide Resistance of Stem-Like Glioblastoma Cells via the MDM2-p53 Axis

et al. 2011

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Overcoming the resistance of glioblastoma cells against temozolomide, the first-line chemotherapeutic agent of choice for newly diagnosed glioblastoma, is a major therapeutic challenge in the management of this deadly brain tumor. The gene encoding O 6 -methylguanine DNA methyltransferase (MGMT), which removes the methyl group attached by temozolomide, is often silenced by promoter methylation in glioblastoma but is nevertheless expressed in a significant fraction of cases and is therefore regarded as one of the most clinically relevant mechanisms of resistance against temozolomide. However, to date, signaling pathways regulating MGMT in MGMT-expressing glioblastoma cells have been poorly delineated. Here in this study, we provide lines of evidence that the mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)-extracellular signal-regulated kinase (ERK)-murine double minute 2 (MDM2)-p53 pathway plays a critical role in the regulation of MGMT expression, using stem-like glioblastoma cells directly derived from patient tumor samples and maintained in the absence of serum, which not only possess stem-like properties but are also known to phenocopy the characteristics of the original tumors from which they are derived. We show that, in stem-like glioblastoma cells, MEK inhibition reduced MDM2 expression and that inhibition of either MEK or MDM2 resulted in p53 activation accompanied by p53-dependent downregulation of MGMT expression. MEK inhibition rendered otherwise resistant stem-like glioblastoma cells sensitive to temozolomide, and combination of MEK inhibitor and temozolomide treatments effectively deprived stem-like glioblastoma cells of their tumorigenic potential. Our findings suggest that targeting of the MEK-ERK-MDM2-p53 pathway in combination with temozolomide could be a novel and promising therapeutic strategy in the treatment of glioblastoma. STEM CELLS

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Section: Resultsmentioning

confidence: 87%

MEK-ERK Signaling Dictates DNA-Repair Gene MGMT Expression and Temozolomide Resistance of Stem-Like Glioblastoma Cells via the MDM2-p53 Axis

et al. 2011

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“…We have checked multiple phospho-p53 antibodies and have not found any change in the phosphorylation of p53 under the influence of BG. In our prior work 48 we have described a mechanism of p53-induced MGMT inhibition which did not rely on activation via phosphorylation. We have shown that restoration of specific p53 function (even in mutated p53 cell lines)…”

Section: Bg (mentioning

confidence: 99%

“…There is an inverse correlation between the levels of MGMT and p53 tumor suppressor protein (46), where wild-type p53 suppresses transcription of MGMT expression (47) by direct binding to the MGMT promoter (48). Unfortunately p53 is often inactivated or suppressed in cancers and restoration of p53 activity remains essential to the success of some treatments.…”

Section: Introductionmentioning

confidence: 99%

MGMT Inhibition Restores ERα Functional Sensitivity to Antiestrogen Therapy

Bobustuc

Smith

Maddipatla

et al. 2012

Mol Med

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Antiestrogen therapy resistance remains a huge stumbling block in the treatment of breast cancer. We have found significant elevation of O 6 methylguanine DNA methyl transferase (MGMT) expression in a small sample of consecutive patients who have failed tamoxifen treatment. Here, we show that tamoxifen resistance is accompanied by upregulation of MGMT. Further we show that administration of the MGMT inhibitor, O 6 -benzylguanine (BG), at nontoxic doses, leads to restoration of a favorable estrogen receptor alpha (ERα) phosphorylation phenotype (high p-ERα Ser167/low p-ERα Ser118), which has been reported to correlate with sensitivity to endocrine therapy and improved survival. We also show BG to be a dual inhibitor of MGMT and ERα. . We also show that BG, alone or in combination therapy, curtails the growth of tamoxifen-resistant breast cancer in vitro and in vivo. In tamoxifen-resistant MCF7 breast cancer xenografts, BG alone or in combination treatment causes significant delay in tumor growth. Immunohistochemistry confirms that BG increases p21 cip1/waf1 and p-ERα Ser167 expression and inhibits MGMT, ERα, p-ERα Ser118 and ki-67 expression. Collectively, our results suggest that MGMT inhibition leads to growth inhibition of tamoxifen-resistant breast cancer in vitro and in vivo and resensitizes tamoxifen-resistant breast cancer cells to antiestrogen therapy. These findings suggest that MGMT inhibition may provide a novel therapeutic strategy for overcoming antiestrogen resistance.

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“…Because overexpression of p53 may suppress MGMT, targeting p53 may render GBM more sensitive to TMZ. Levetiracetam is often used in GBM patients to manage seizures, but its use may further benefit patients by augmenting p53-mediated MGMT suppression [61].…”

Section: O6-benzylguaninementioning

confidence: 99%