Temozolomide competes for P-glycoprotein and contributes to chemoresistance in glioblastoma cells

Munoz, Jessian L.; Walker, Nykia D.; Scotto, Kathleen W.; Rameshwar, Pranela

doi:10.1016/j.canlet.2015.07.013

Cited by 86 publications

(60 citation statements)

References 23 publications

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“…TMZ, as frontline chemotherapeutic agent for GB, is frequently limited in durability of treatment response by drug resistance development. Though diverse mechanisms toward TMZ resistance, for example, DNA O 6 -methylguanine methyltransferase (MGMT), DNA mismatch repair (MMR), base excision repair (BER), ATP-binding cassette (ABC) protein family, have been demonstrated so far, 36, 37, 38, 39, 40 more effort is still needed for identifying novel mechanisms underlying acquired TMZ resistance. Herein, we show that TMZ treatment could activate the TGF- β /CTGF axis pathway with Smad and ERK1/2 signal-dependent manner that contribute to the acquired TMZ resistance.…”

Section: Discussionmentioning

confidence: 99%

Connective tissue growth factor promotes temozolomide resistance in glioblastoma through TGF-β1-dependent activation of Smad/ERK signaling

Zeng¹,

Zhao²,

Xu³

et al. 2017

Cell Death Dis

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Limited benefits and clinical utility of temozolomide (TMZ) for glioblastoma (GB) are frequently compromised by the development of acquired drug resistance. Overcoming TMZ resistance and uncovering the underlying mechanisms are challenges faced during GB chemotherapy. In this study, we reported that connective tissue growth factor (CTGF) was associated with GB chemoresistance and significantly upregulated in TMZ-treated GB cells. CTGF knockdown promoted TMZ-induced cell apoptosis and enhanced chemosensitivity, whereas its overexpression markedly conferred TMZ resistance in vitro and in vivo. Moreover, CTGF promoted TMZ resistance through stem-like properties acquisition and CD44 interference reversed the CTGF-induced TMZ resistance. Mechanistically, further investigation revealed that the TMZ-induced CTGF upregulation was tissue growth factor (TGF-β) dependent, and regulated by TGF-β1 activation through Smad and ERK1/2 signaling. Together, our results suggest a pivotal role of CTGF-mediated TMZ resistance through TGF-β1-dependent activation of Smad/ERK signaling pathways. These data provide us insights for identifying potential targets that are beneficial for overcoming TMZ resistance in GB.

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Section: Discussionmentioning

confidence: 99%

Connective tissue growth factor promotes temozolomide resistance in glioblastoma through TGF-β1-dependent activation of Smad/ERK signaling

Zeng¹,

Zhao²,

Xu³

et al. 2017

Cell Death Dis

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“…The TR cells were generated by repetitive pulse exposure of U87 and U251 GBM cells to TMZ (48 h every 2 weeks) and with increasing TMZ concentrations for 6 months. For TR phenotype maintenance, U87TR and U251TR cells were alternately treated with TMZ (500 µ M) for 48 h. The corresponding methods were mainly based on the previous study of Monoz et al (15–17) and with minor adjustment in this study. The parental and TR cells were maintained in DMEM (Hyclone, USA) with 10% (v/v) FBS (Hyclone) and 1% (v/v) penicillin/streptomycin (Gibco, USA) at 37°C in 5% CO 2 humidified air incubator (Thermo Scientific, USA).…”

Section: Methodsmentioning

confidence: 99%

Genomic profiling of long non-coding RNA and mRNA expression associated with acquired temozolomide resistance in glioblastoma cells

Zeng¹,

Xu²,

Liu

et al. 2017

International Journal of Oncology

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Temozolomide (TMZ) is an alkylating chemotherapeutic agent widely used in anti-glioma treatment. However, acquired TMZ resistance represents a major clinical challenge that leads to tumor relapse or progress. This study investigated the genomic profiles including long non-coding RNA (lncRNA) and mRNA expression associated with acquired TMZ resistance in glioblastoma (GBM) cells in vitro. The TMZ-resistant (TR) of GBM sub-cell lines were established through repetitive exposure to increasing TMZ concentrations in vitro. The differentially expressed lncRNAs and mRNAs between the parental U87 and U87TR cells were detected by human lncRNA microarray method. In this study, we identified 2,692 distinct lncRNAs demonstrating >2-fold differential expression with 1,383 lncRNAs upregulated and 1,309 lncRNAs downregulated. Moreover, 4,886 differential mRNAs displayed 2,933 mRNAs upregulated and 1,953 mRNAs downregulated. Further lncRNA classification and subgroup analysis revealed the potential functions of the lncRNA-mRNA relationship associated with the acquired TMZ resistance. Gene ontology and pathway analysis on mRNAs showed significant biological regulatory genes and pathways involved in acquired TMZ resistance. Moreover, we found the ECM-receptor interaction pathway was significantly downregulated and ECM related collagen I, fibronectin, laminin and CD44 were closely associated with the TR phenotype in vitro. Our findings indicate that the dysregulated lncRNAs and mRNAs identified in this work may provide novel targets for overcoming acquired TMZ resistance in GBM chemotherapy.

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“…In both acquired and intrinsic temozolomide resistance, MGMT expression is up-regulated, thus rendering DNA damage by temozolomide ineffective (4). Although not as crucial as MGMT, P-glycoprotein expression contributes to temozolomide resistance because temozolomide is a good substrate of this efflux pump (6). Mechanisms of intrinsic resistance are seemingly different from mechanisms of acquired resistance, although they share various key similarities (3).…”

Section: Discussionmentioning

confidence: 99%

“…Commonly, in temozolomide resistance, O 6 methylguanine DNA transferase (MGMT) repairs the methylation of guanine at the O 6 position, thus rendering temozolomide incapable of inducing apoptosis (5). Additionally, up-regulation of the drug efflux pump Pglycoprotein has been linked to temozolomide resistance (6).…”

mentioning

confidence: 99%

Probing the Oncolytic and Chemosensitizing Effects of Dihydrotanshinone in an In Vitro Glioblastoma Model

Radin

Leonardi²

2017

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Temozolomide competes for P-glycoprotein and contributes to chemoresistance in glioblastoma cells

Cited by 86 publications

References 23 publications

Connective tissue growth factor promotes temozolomide resistance in glioblastoma through TGF-β1-dependent activation of Smad/ERK signaling

Connective tissue growth factor promotes temozolomide resistance in glioblastoma through TGF-β1-dependent activation of Smad/ERK signaling

Genomic profiling of long non-coding RNA and mRNA expression associated with acquired temozolomide resistance in glioblastoma cells

Probing the Oncolytic and Chemosensitizing Effects of Dihydrotanshinone in an In Vitro Glioblastoma Model

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