Chemotherapeutic effect of tamoxifen on temozolomide-resistant gliomas

He, Weiliang; Liu, Ran; Yang, Shao Hua; Yuan, Fang

doi:10.1097/cad.0000000000000197

Cited by 35 publications

(25 citation statements)

References 23 publications

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“…Regarding A172 cells, He et al [25] described that TMZ concentrations of 0.4, 4, or 40 lM did not influence cell viability after treatment for two days, which is in agreement with our findings from the same glioblastoma cell lineage. After treatment with SAS alone, we observed reduced cell viability after 3 and 5 days; the effect on viability compared to that of 0.1 % DMSO was particularly intense after 5 days, reaching a reduction of 52.7 %.…”

Section: Discussionsupporting

confidence: 93%

Sulfasalazine intensifies temozolomide cytotoxicity in human glioblastoma cells

et al. 2016

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Temozolomide (TMZ) is an alkylating agent used to treat glioblastoma. This tumor type synthesizes the antioxidant glutathione through system X c (-) , which is inhibited by sulfasalazine (SAS). We exposed A172 and T98G human glioblastoma cells to a presumably clinically relevant concentration of TMZ (25 µM) and/or 0.5 mM SAS for 1, 3, or 5 days and assessed cell viability. For both cell lines, TMZ alone did not alter viability at any time point, while the coadministration of TMZ and SAS significantly reduced cell viability after 5 days. The drug combination exerted a synergistic effect on A172 cells after 3 and 5 days. Therefore, this particular lineage was subjected to complementary analyses on the genetic (transcriptome) and functional (glutathione and proliferating cell nuclear antigen (PCNA) protein) levels. Cellular pathways containing differentially expressed genes related to the cell cycle were modified by TMZ alone. On the other hand, SAS regulated pathways associated with glutathione metabolism and synthesis, irrespective of TMZ. Moreover, SAS, but not TMZ, depleted the total glutathione level. Compared with the vehicle-treated cells, the level of PCNA protein was lower in cells treated with TMZ alone or in combination with SAS. In conclusion, our data showed that the association of TMZ and SAS is cytotoxic to T98G and A172 cells, thus providing useful insights for improving TMZ clinical efficacy through testing this novel drug combination. Moreover, the present study not only reports original information on differential gene expression in glioblastoma cells exposed to TMZ and/or SAS but also describes an antiproliferative effect of TMZ, which has not yet been observed in A172 cells.

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Section: Discussionsupporting

confidence: 93%

Sulfasalazine intensifies temozolomide cytotoxicity in human glioblastoma cells

et al. 2016

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“…38 The estrogen receptor antagonist tamoxifen was shown to induce cell death in glioma cells 39 and has been proposed as a potential chemotherapeutic agent in temozolomide-resistant glioblastoma. 40 Our results provide a potential molecular basis for this indication of tamoxifen, especially given that most patients with recurrent glioblastoma are further exposed to dexamethasone. NUPR1, the most inhibited dexamethasone-dependent upstream regulator we found, is involved in a variety of stress-related functions in non-cancer conditions 41 and as a tumor suppressor in prostate cancer.…”

Section: Discussionmentioning

confidence: 80%

A Dexamethasone-regulated Gene Signature Is Prognostic for Poor Survival in Glioblastoma Patients

Luedi

Singh²,

Mosley³

et al. 2017

Journal of Neurosurgical Anesthesiology

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Background Dexamethasone is reported to induce both tumor-suppressive and tumor-promoting effects. The purpose of this study was to identify the genomic impact of dexamethasone in glioblastoma stem cell (GSC) lines and its prognostic value; furthermore, to identify drugs that can counter these side effects of dexamethasone exposure. Methods We utilized three independent GSC lines with tumorigenic potential for this study. Whole-genome expression profiling and pathway analyses were done with dexamethasone-exposed and control cells. GSCs were also co-exposed to dexamethasone and temozolomide. Risk scores were calculated for most affected genes, and their associations with survival in TCGA and REMBRANDT databases. In silico connectivity Map analysis identified camptothecin as antagonist to dexamethasone induced negative effects. Results Pathway analyses predicted an activation of dexamethasone network (z-score:2.908). Top activated canonical pathways included ‘role of BRCA1 in DNA damage response’ (p=1.07E-04). GSCs were protected against temozolomide-induced apoptosis when co-incubated with dexamethasone. Altered cellular functions included cell-movement, cell-survival, and apoptosis with z-scores of 2.815, 5.137, and −3.122 respectively. CEBPB was activated in a dose dependent manner specifically in slow-dividing ‘stem-like’ cells. CEBPB was activated in dexamethasone-treated orthotopic tumors. Patients with high risk score had significantly shorter survival. Camptothecin was validated as potential partial neutralizer of dexamethasone effects. Conclusions Dexamethasone exposure induces a genetic program and CEBPB expression in GSCs that adversely affects key cellular functions and response to therapeutics. High risk scores associated with these genes have negative prognostic value. Our findings further suggest camptothecin as a potential neutralizer of adverse dexamethasone-mediated effects.

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“…Two major pathways that regulate apoptosis are the cell death receptormediated extrinsic pathway and the mitochondrial-mediated intrinsic apoptotic pathway (Roshan et al, 2014). Cell death also occurs after cytotoxic drug treatment in various cancers, and apoptosis induction is the main strategy of many anticancer drugs (He et al, 2015). To date, the development of anticancer drugs has focused on inititating apoptosis in tumor cells.…”

Section: Discussionmentioning

confidence: 99%

Borax-induced apoptosis in HepG2 cells involves p53, Bcl-2, and Bax

et al. 2016

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ABSTRACT. Borax, a boron compound and a salt of boric acid, is known to inhibit the growth of tumor cells. HepG2 cells have been shown to be clearly susceptible to the anti-proliferative effects of borax. However, the specific mechanisms regulating this effect are poorly understood. This study aimed to investigate the pathways underlying the growth inhibition induced by borax in HepG2 cells. The effects of borax on HepG2 cell viability were characterized using MTT. Apoptosis was also verified by annexin V/propidium iodide staining. JC-1 dye and western blotting techniques were used to measure mitochondrial membrane potential and p53, Bax, and Bcl-2 protein expression, respectively. Relevant mRNA levels were measured by qRT-PCR. Borax inhibited the proliferation of HepG2 cells in a time-and dosedependent manner in vitro. The apoptotic process triggered by borax involved the upregulation of p53 and Bax and the downregulation of Bcl-2, which was confirmed by a change in the mitochondrial membrane potential. These results elucidate a borax-induced apoptotic

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Chemotherapeutic effect of tamoxifen on temozolomide-resistant gliomas

Cited by 35 publications

References 23 publications

Sulfasalazine intensifies temozolomide cytotoxicity in human glioblastoma cells

Sulfasalazine intensifies temozolomide cytotoxicity in human glioblastoma cells

A Dexamethasone-regulated Gene Signature Is Prognostic for Poor Survival in Glioblastoma Patients

Borax-induced apoptosis in HepG2 cells involves p53, Bcl-2, and Bax

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