The Correlation between Promoter Methylation Status and the Expression Level of O6-Methylguanine-DNA Methyltransferase in Recurrent Glioma

Suzuki, Tamaki; Nakada, Mitsutoshi; Yoshida, Yuya; Nambu, E; Furuyama, Natsuki; Kita, Daisuke; Hayashi, Yutaka; Hayashi, Yasuhiko; Hamada, Jun-ichiro

doi:10.1093/jjco/hyq224

Cited by 10 publications

(16 citation statements)

References 26 publications

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“…Sodium bisulfite conversion of 1 μg DNA was performed using an EpiTect Bisulfite Kit (QIAGEN) according to the manufacture's protocol. Methylation-specific PCR of bisulfite-converted DNA was carried out by a nested, two-stage PCR approach as described previously [59] using GeneAmp PCR System 2700 (Applied Biosystems, Foster city, CA, USA). U87 and U138 cell lines were used as methylated and unmethylated controls, respectively.…”

Section: Methodsmentioning

confidence: 99%

Biological basis and clinical study of glycogen synthase kinase- 3β-targeted therapy by drug repositioning for glioblastoma

et al. 2017

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BackgroundGlycogen synthase kinase (GSK)-3β has emerged as an appealing therapeutic target for glioblastoma (GBM). Here, we investigated the therapeutic effect of the current approved drugs against GBM via inhibition of GSK3β activity both, in experimental setting and in a clinical study for recurrent GBM patients by repositioning existent drugs in combination with temozolomide (TMZ).Materials and MethodsProgression-free and overall survival rates were compared between patients with low or high expression of active GSK3β in the primary tumor. GBM cells and a mouse model were examined for the effects of GSK3β-inhibitory drugs, cimetidine, lithium, olanzapine, and valproate. The safety and efficacy of the cocktail of these drugs (CLOVA cocktail) in combination with TMZ were tested in the mouse model and in a clinical study for recurrent GBM patients.ResultsActivation of GSK3β in the tumor inversely correlated with patient survival as an independent prognostic factor. CLOVA cocktail significantly inhibited cell invasion and proliferation. The patients treated with CLOVA cocktail in combination with TMZ showed increased survival compared to the control group treated with TMZ alone.ConclusionsRepositioning of the GSK3β-inhibitory drugs improved the prognosis of refractory GBM patients with active GSK3β in tumors. Combination of CLOVA cocktail and TMZ is a promising approach for recurrent GBM.

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Section: Methodsmentioning

confidence: 99%

Biological basis and clinical study of glycogen synthase kinase- 3β-targeted therapy by drug repositioning for glioblastoma

et al. 2017

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“…The methylation status of the MGMT promoter were evaluated by methylation-specific PCR (MSP) assay as described previously4546. Genomic DNA was extracted from the cells using a QIAamp DNA Mini Kit (Qiagen).…”

Section: Methodsmentioning

confidence: 99%

BACH1 Promotes Temozolomide Resistance in Glioblastoma through Antagonizing the Function of p53

Nie

Jin

et al. 2016

Sci Rep

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The acquisition of drug resistance is a persistent clinical problem limiting the successful treatment of glioblastoma (GBM). However, the molecular mechanisms by which initially chemoresponsive tumors develop therapeutic resistance remain poorly understood. In this study, we report that BACH1, a heme-binding protein that participates in transcriptional repression or activation, was significantly upregulated in glioblastoma tissues. Overexpression of BACH1 in GBM cells conferred resistance to temozolomide, whereas its inhibition markedly sensitized resistant cells to temozolomide in vitro and in vivo. Further investigation revealed that BACH1 activation significantly enhanced the expression of MGMT, and depletion of p53 disrupted the effects of BACH1 on MGMT and temozolomide resistance. P53 sequesters SP1 to prevent its binding to the MGMT promoter region and thus inhibits MGMT expression. Moreover, BACH1 overexpression impaired the association between p53 and SP1 via competitive binding p53, and antagonized the impact of p53 on MGMT expression. Finally, we found that BACH1 low expression correlated with better prognosis in GBM patients undergoing temozolomide therapy, especially in patients with wild-type TP53. Collectively, our findings identify a potential mechanism by which wild-type TP53 GBM cells develop resistance to temozolomide and suggest that targeting this pathway may be beneficial for overcoming resistance.

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“…Next, our model suggests that TMZ has an inhibitory effect on maintenance methylation of MGMT after cell division. Finally, incorporating this inhibitory effect, we study the optimal number of TMZ doses per adjuvant cycle for GBM patients with high and low levels of MGMT methylation at diagnosis.Studies have compared MGMT promoter methylation in newly diagnosed tumors to matched recurrence samples following TMZ treatment [6,37,22,11]. These studies provide evidence of a downward shift in the MGMT promoter methylation percentage during treatment.…”

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confidence: 99%

“…These studies provide evidence of a downward shift in the MGMT promoter methylation percentage during treatment. For example, in [6], 8 of 13 patients transitioned from an MGMT-methylated primary tumor to an unmethylated recurrent tumor after treatment, and in [37], it was reported that 10 of the 13 patients switched from a methylated primary tumor to an unmethylated recurrent tumor. In [11], authors observed that 39.1% of pretreatment GBM and 5.3% of recurrences were promoter methylated, in addition to an observed increase of MGMT activity in the recurrences.…”

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Glioblastoma recurrence and the role of MGMT promoter methylation

Storey

Leder

Hawkins-Daarud

et al. 2018

Preprint

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Tumor recurrence in glioblastoma multiforme (GBM) is often attributed to acquired resistance to the standard chemotherapeutic agent temozolomide (TMZ). Promoter methylation of the DNA repair gene MGMT has been associated with sensitivity to TMZ, while increased expression of MGMT has been associated with TMZ resistance. Clinical studies have observed a downward shift in MGMT methylation percentage from primary to recurrent stage tumors. However, the evolutionary processes driving this shift, and more generally the emergence and growth of TMZ-resistant tumor subpopulations, are still poorly understood. Here we develop a mathematical model, parameterized using clinical and experimental data, to investigate the role of MGMT methylation in TMZ resistance during the standard treatment regimen for GBM (surgery, chemotherapy and radiation). We first find that the observed downward shift in MGMT promoter methylation status between detection and recurrence cannot be explained solely by evolutionary selection. Next, our model suggests that TMZ has an inhibitory effect on maintenance methylation of MGMT after cell division. Finally, incorporating this inhibitory effect, we study the optimal number of TMZ doses per adjuvant cycle for GBM patients with high and low levels of MGMT methylation at diagnosis.

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The Correlation between Promoter Methylation Status and the Expression Level of O6-Methylguanine-DNA Methyltransferase in Recurrent Glioma

Abstract: Our results give the evidence that the increase of O(6)-methylguanine-DNA methyltransferase mRNA expression caused by methylation changes in recurrence may be associated with chemoresistance in the recurrent glioma.

Cited by 10 publications

References 26 publications

Biological basis and clinical study of glycogen synthase kinase- 3β-targeted therapy by drug repositioning for glioblastoma

Biological basis and clinical study of glycogen synthase kinase- 3β-targeted therapy by drug repositioning for glioblastoma

BACH1 Promotes Temozolomide Resistance in Glioblastoma through Antagonizing the Function of p53

Glioblastoma recurrence and the role of MGMT promoter methylation

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