Gene expression profiles of 1-(4-amino-2-methyl-5-pyrimidinyl)-methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU)-resistant C6 rat glioma cells

Nakagawa, Takao; Kubota, Toshihiko; Ido, Kazunori; Sakuma, Takahiro; Matsuda, Ken

doi:10.1007/s11060-006-9143-z

Cited by 4 publications

(2 citation statements)

References 25 publications

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“…GFAP‐negative cells have greater proliferate potency than positive cells, and down‐regulation of GFAP expression was also found in 1‐(4‐amino‐2‐methyl‐5‐pyrimidinyl)‐methyl‐3‐(2‐chloroethyl)‐3‐nitrosoureahydrochloride (ACNU)‐resistant C6 glioma cells (Hara et al. 1991; Nakagawa et al. 2006).…”

Section: Discussionmentioning

confidence: 99%

Down‐regulation of lipocalin 2 contributes to chemoresistance in glioblastoma cells

Zheng¹,

Lee²,

Yin³

et al. 2009

Journal of Neurochemistry

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Malignant gliomas are the most common primary brain tumor and have a poor clinical prognosis. 1, 3‐Bis (2‐chloroethyl)‐1‐nitrosourea (BCNU) is an alkylating agent that is commonly used in glioma therapy. However, BCNU chemotherapy often fails due to drug resistance. To gain better understanding of molecular mechanisms underlying the drug resistance of glioma, a BCNU‐resistant variant (C6R) of C6 rat glioma cells was selected and characterized. The established C6R cells were resistant to BCNU‐induced cell death and cell cycle arrest as confirmed by 3‐(4, 5‐dimethylthiazol‐2‐yl)‐2, 5‐diphenyltetrazolium bromide reduction assay and flow cytometric analysis of DNA content. C6R cells showed an increased expression of common drug resistance‐related genes such as O6‐methylguanine‐DNA methyltransferase and multiple drug resistance 1. In contrast, C6R cells showed a decreased expression of glial fibrillary acidic protein, therefore, displaying shorter cellular processes compared with parental C6 cells. More importantly, in conjunction with the morphological changes, the expression of lipocalin‐2 (lcn2), a 25‐kDa secreted proapoptotic protein, was markedly reduced in the BCNU‐resistant C6R cells. However, there was no significant change in the expression of lcn2 receptors. Addition of recombinant LCN2 protein or introduction of lcn2 cDNA significantly increased the sensitivity of C6 cells and human glioma cells to BCNU or other anticancer drugs, while knockdown of lcn2 expression by antisense cDNA transfection decreased the sensitivity. When lcn2 was re‐expressed in C6R cells, the BCNU sensitivity was restored. Lcn2 enhanced BCNU‐induced Akt dephosphorylation providing a molecular basis of apoptosis sensitization. These results suggest that LCN2 protein may be involved in glioma drug resistance and may provide a new approach to sensitizing glioblastoma to chemotherapy.

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Section: Discussionmentioning

confidence: 99%

Down‐regulation of lipocalin 2 contributes to chemoresistance in glioblastoma cells

Zheng¹,

Lee²,

Yin³

et al. 2009

Journal of Neurochemistry

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“…These data suggest that incomplete depletion of MGMT is not sufficient to overcome the resistance and that additional optimization will be required for the complete reversion of drug resistance (Manome et al, 2002). C6 rat glioma cells rendered resistant to antitumor nitrosoureas like BCNU have a protein expression profile that suggests a more aggressive, less differentiated behavior (Nakagawa et al, 2006). BCNU plus DNA-alkyltransferase inhibitor is not an effective regimen for nitrosourea-resistant glioma (Quinn et al, 2002).…”

Section: Gliomas and Glioblastomasmentioning

confidence: 99%

Pharmacotherapy for adults with tumors of the central nervous system

Schor

2009

Pharmacology & Therapeutics

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Tumors of the adult central nervous system are among the most common and most chemoresistant neoplasms. Malignant tumors of the brain and spinal cord collectively account for approximately 1.3% of all cancers and 2.2% of all cancer-related deaths. Novel pharmacological approaches to nervous system tumors are urgently needed. This review presents the current approaches and challenges to successful pharmacotherapy of adults with malignant tumors of the central nervous system and discusses novel approaches aimed at overcoming these challenges.

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Effects of Chemotherapeutics on Organotypic Corticostriatal Slice Cultures Identified by A Panel of Fluorescent and Immunohistochemical Markers

et al. 2011

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Effects of chemotherapeutics on glioma cell lines and spheroids are usually investigated without evaluating the effects of chemotherapeutics on normal brain tissue. To perform such investigations, the aim of this study was to establish a panel of markers for detection of general cell death and more specific neuronal and glial degeneration induced by chemotherapeutics in organotypic rat corticostriatal slice cultures. The slice cultures were exposed to the alkylating agents temozolomide (TMZ) and nimustine (ACNU), the tyrosine kinase inhibitor imatinib mesylate (IM) and the microtubule-destabilizing agent vincristine (VCR). Densitometric measurements of uptake of the fluorescent dye propidium iodide (PI) were used for quantifying cellular degeneration. Moreover, paraffin sections were hematoxylin eosine stained and immunostained for the neuronal marker microtubule-associated protein 2 (MAP2), the astroglial marker glial fibrillary acidic protein (GFAP), and the oligodendroglial marker p25α. The results showed that the supposed clinically relevant drug concentrations were non-toxic. However, a time dependent increase in PI uptake was observed for high drug concentrations, except for TMZ, where no toxicity was observed. Corresponding immunostaining showed loss of MAP2 and increased expression of GFAP and p25α for cultures exposed to 1,000 nM VCR. Cultures exposed to high concentrations of ACNU and IM disintegrated, leaving no tissue for histology. In conclusion, corticostriatal slice cultures and the established panel of markers represent an excellent tool for detecting toxicity induced by chemotherapeutics. Toxicity was not detected at clinical concentrations, but high concentrations with toxic effects were identified suggesting that some of the earlier identified anti-cancer effects are general cytotoxic effects and not specific anti-cancer effects.

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Gene expression profiles of 1-(4-amino-2-methyl-5-pyrimidinyl)-methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU)-resistant C6 rat glioma cells

Cited by 4 publications

References 25 publications

Down‐regulation of lipocalin 2 contributes to chemoresistance in glioblastoma cells

Down‐regulation of lipocalin 2 contributes to chemoresistance in glioblastoma cells

Pharmacotherapy for adults with tumors of the central nervous system

Effects of Chemotherapeutics on Organotypic Corticostriatal Slice Cultures Identified by A Panel of Fluorescent and Immunohistochemical Markers

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