Genetic alterations associated with acquired temozolomide resistance in SNB-19, a human glioma cell line

Auger, Nathalie; Thillet, Joëlle; Wanherdrick, Krystell; Idbaïh, Ahmed; Legrier, Marie-Emmanuelle; Dutrillaux, Bernard; Sanson, Marc; Poupon, Marie‐France

doi:10.1158/1535-7163.mct-05-0428

Cited by 55 publications

(49 citation statements)

References 50 publications

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“…In our data, methylation status of the promoter region was not changed (fully methylated in both U251Wt and U251R cells), suggesting that MGMT expression is not involved in the acquired TMZ resistance in GBM. This is consistent with a previous report by Auger et al [33] in which SNB-19 glioma cells and their resistant variants were used. Other mechanism may be involved in the step of obtaining the resistance.…”

Section: Discussionsupporting

confidence: 93%

miR-195, miR-455-3p and miR-10a∗ are implicated in acquired temozolomide resistance in glioblastoma multiforme cells

Ujifuku¹,

Mitsutake²,

Takakura³

et al. 2010

Cancer Letters

210

137

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Running title: miRNAs and temozolomide resistance in glioblastoma Key words: glioblastoma, resistance, microRNA,, miR-10a*, temozolomide. ABSTRACTTo identify microRNAs (miRNAs) specifically involved in the acquisition of temozolomide (TMZ) resistance in glioblastoma multiforme (GBM), we first established a resistant variant, U251R cells from TMZ-sensitive GBM cell line, U251MG. We then performed a comprehensive analysis of miRNA expressions in U251R and parental cells using miRNA microarrays. miR-195, miR-455-3p and miR-10a* were the three most up-regulated miRNAs in the resistant cells. To investigate the functional role of these miRNAs in TMZ resistance, U251R cells were transfected with miRNA inhibitors consisting of DNA/LNA hybrid oligonucleotides. Suppression of miR-455-3p or miR-10a* had no effect on cell growth, but showed modest cell killing effect in the presence of TMZ. On the other hand, knockdown of miR-195 alone displayed moderate cell killing effect, and combination with TMZ strongly enhanced the effect. In addition, using in silico analysis combined with cDNA microarray experiment, we present possible mRNA targets of these miRNAs. In conclusion, our findings suggest that those miRNAs may play a role in acquired TMZ resistance and could be a novel target for recurrent GBM treatment.

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Section: Discussionsupporting

confidence: 93%

miR-195, miR-455-3p and miR-10a∗ are implicated in acquired temozolomide resistance in glioblastoma multiforme cells

Ujifuku¹,

Mitsutake²,

Takakura³

et al. 2010

Cancer Letters

210

137

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“…As a DNA repair enzyme, MGMT is a protein that can transfer the alkylated group of methylguanine from the O 6 position to its own cysteine residue (4,5,15), so that the TMZ-induced guanine damage in DNA can be repaired. Previous studies have demonstrated that the levels of MGMT vary considerably in glioma cells, which can be divided into the MGMT repair-deficient cells and cells with a sufficient MGMT repair (16).…”

Section: Discussionmentioning

confidence: 99%

“…Although maximal surgical resection combined with TMZ therapy and irradiation has significantly improved the quality of life and prolonged the survival time of patients with GBM, the overall clinical prognosis remains unsatisfactory due to intrinsic or acquired tumor cell resistance to TMZ (3). Previous studies have demonstrated that O 6 -methylguanine-DNA methyltransferase (MGMT) is the main factor responsible for chemoresistance to TMZ in GBM cells (4,5). However, the molecular mechanism of TMZ resistance is more complex than a simple dependence on MGMT expression.…”

Section: Introductionmentioning

confidence: 99%

NF-κB inhibitor reverses temozolomide resistance in human glioma TR/U251 cells

et al. 2015

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Abstract. Glioblastoma multiforme (GBM) demonstrates an unsatisfactory clinical prognosis due to the intrinsic or acquired resistance to temozolomide (TMZ) exhibited by the tumors. One possible cause of TMZ resistance in GBM is the overexpression of O 6 -methylguanine-DNA methyltransferase (MGMT), which can repair the TMZ-induced guanine damage in DNA. Additionally, excessive activated NF-κB is reported to be a component of the major inflammatory transcription pathway that is associated with TMZ resistance in GBM. However, the association between the NF-κB pathway and MGMT expression in GBM cells is unknown. Therefore, in the present study, the TMZ resistant (TR) U251 cell line (TR/U251) was successfully constructed to detect how the TR/U251 cell line and the parental U251 cell line each interact with TMZ in vitro. The TR/U251 cells were approximately five times more resistant to TMZ compared with the parental cells. Furthermore, it was found that the NF-κB inhibitor BAY 11-7082 suppressed the expression of MGMT in TR/U251 cells and enhanced TMZ-induced cytotoxicity and apoptosis, thereby indicating that the NF-κB pathway and MGMT interact to promote TMZ resistance. The inhibition of NF-κB may be a promising strategy to reverse drug resistance in TR glioma cells. The present results propose a potential mechanism for using the NF-κB inhibitor BAY 11-7082 as a potential therapy for the treatment of TR glioma. Although BAY 11-7082 is a well-known NF-κB inhibitor, the present study further investigated its underlying mechanisms through a series of new experiments.

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“…On the other hand, defective DNA MMR can result in tolerance to TMZ regardless of MGMT activity and continuance of DNA replication (4,5). However, some studies have demonstrated resistance to TMZ that was independent of such candidates, suggesting that other major mechanisms were involved in the resistance to TMZ (4,6). Furthermore, tumor chemotherapy resistance may be very complicated, often multifactorial and with many genes involved.…”

Section: Introductionmentioning

confidence: 99%

Gene expression profiling predicts response to temozolomide in malignant gliomas

Yoshino

Ogino²,

Yachi³

et al. 2010

Int J Oncol

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Abstract. Malignant gliomas are highly lethal neoplasms that cannot be cured with currently available therapies. Temozolomide (TMZ) is a recently introduced alkylating agent that has yielded significant benefits and become a key agent in the treatment of high-grade gliomas. However, its survival benefit remains unsatisfactory. Understanding the molecular basis of TMZ sensitivity/resistance is necessary for improving the treatment outcome by devising strategies that are able to circumvent primary drug resistance. We therefore combined the in vitro TMZ response with microarray gene expression data to identify genes that could potentially be used to predict the response of malignant gliomas to TMZ therapy. We first obtained the individual IC 50 values for TMZ in seven malignant glioma cell lines (A-172, AM-38, T98G, U-87MG, U-138MG, U-251MG and YH-13) and then identified the genes whose expression correlated most highly with TMZ sensitivity employing a cDNA microarray. We present here a list of the most highly up-regulated and down-regulated genes which may be involved in conferring TMZ sensitivity/resistance in malignant gliomas, although most of the genes have not been implicated as a causal factor in the TMZ response except MGMT. We also demonstrated and confirmed the MGMT methylation status, quantitative MGMT mRNA levels, and MGMT protein expression levels in TMZ resistant glioma cells in vitro. Our results are thus consistent with previous studies and suggest that a dominant mechanism conferring sensitivity/resistance to TMZ exists in malignant glioma cells. Although the present study dose have several limitations, our reported candidate genes could represent not only potential molecular markers for TMZ sensitivity/resistance but also chemotherapy targets. Furthermore, the present study could provide a foundation for alternative therapeutic strategies including novel combination treatments that incorporate additional reagents directed at overcoming resistance to TMZ.

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Genetic alterations associated with acquired temozolomide resistance in SNB-19, a human glioma cell line

Cited by 55 publications

References 50 publications

miR-195, miR-455-3p and miR-10a∗ are implicated in acquired temozolomide resistance in glioblastoma multiforme cells

miR-195, miR-455-3p and miR-10a∗ are implicated in acquired temozolomide resistance in glioblastoma multiforme cells

NF-κB inhibitor reverses temozolomide resistance in human glioma TR/U251 cells

Gene expression profiling predicts response to temozolomide in malignant gliomas

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