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Effect of cytosine arabinoside on cerebellar neurofilaments during development: A sexual dimorphism.

ABSTRACT: Previous reports suggest that the resistance of neuronal cytoskeleton to drug toxicity may vary with age and gender. The aim of the present study was to assess the impact of cytosine arabinoside (AraC) treatment on neurofilament (NF) levels and phosphorylation status in the developing cerebellum of male, female and testosterone propionate (1.25 mg/rat)-androgenized female rats. AraC (200 mg/kg bw) was administered from postnatal day (PND) 14-16 and changes in the level and phosphorylation of NFs were detected at PND 16 by Western blot analysis. The drug had no effect in male pups, while it increased the non-phosphorylated NF subunits of medium and low molecular weight in females. Androgenization of females prevented the AraC-induced increase in NF subunits. The levels of estrogen receptor beta (ER-?), known to mediate neuroprotective actions of estrogens in the brain, were significantly higher in the developing female cerebellum, as compared to males and androgenized females. These data show that the neurofilament cytoskeleton in the developing rat cerebellum exhibits resistance to AraC that appears sexually dimorphic. In young males the resistance is exemplified by a lack of responsiveness, whereas in juvenile females it is presented by an androgenization-sensitive NF upregulation.

SUBMITTER: Koros C

PROVIDER: S-EPMC5598478 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Effect of cytosine arabinoside on cerebellar neurofilaments during development: A sexual dimorphism.

Koros Christos C Kitraki Efthymia E

Toxicology reports 20140906

Previous reports suggest that the resistance of neuronal cytoskeleton to drug toxicity may vary with age and gender. The aim of the present study was to assess the impact of cytosine arabinoside (AraC) treatment on neurofilament (NF) levels and phosphorylation status in the developing cerebellum of male, female and testosterone propionate (1.25 mg/rat)-androgenized female rats. AraC (200 mg/kg bw) was administered from postnatal day (PND) 14-16 and changes in the level and phosphorylation of NFs ...[more]

PMID: 28962278

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Project description:BackgroundThe presence of tumor-specific mutations in the cancer genome represents a potential opportunity for pharmacologic intervention to therapeutic benefit. Unfortunately, many classes of oncoproteins (e.g., transcription factors) are not amenable to conventional small-molecule screening. Despite the identification of tumor-specific somatic mutations, most cancer therapy still utilizes nonspecific, cytotoxic drugs. One illustrative example is the treatment of Ewing sarcoma. Although the EWS/FLI oncoprotein, present in the vast majority of Ewing tumors, was characterized over ten years ago, it has never been exploited as a target of therapy. Previously, this target has been intractable to modulation with traditional small-molecule library screening approaches. Here we describe a gene expression-based approach to identify compounds that induce a signature of EWS/FLI attenuation. We hypothesize that screening small-molecule libraries highly enriched for FDA-approved drugs will provide a more rapid path to clinical application.Methods and findingsA gene expression signature for the EWS/FLI off state was determined with microarray expression profiling of Ewing sarcoma cell lines with EWS/FLI-directed RNA interference. A small-molecule library enriched for FDA-approved drugs was screened with a high-throughput, ligation-mediated amplification assay with a fluorescent, bead-based detection. Screening identified cytosine arabinoside (ARA-C) as a modulator of EWS/FLI. ARA-C reduced EWS/FLI protein abundance and accordingly diminished cell viability and transformation and abrogated tumor growth in a xenograft model. Given the poor outcomes of many patients with Ewing sarcoma and the well-established ARA-C safety profile, clinical trials testing ARA-C are warranted.ConclusionsWe demonstrate that a gene expression-based approach to small-molecule library screening can identify, for rapid clinical testing, candidate drugs that modulate previously intractable targets. Furthermore, this is a generic approach that can, in principle, be applied to the identification of modulators of any tumor-associated oncoprotein in the rare pediatric malignancies, but also in the more common adult cancers.

Dataset Information

Effect of cytosine arabinoside on cerebellar neurofilaments during development: A sexual dimorphism.

Publications

Effect of cytosine arabinoside on cerebellar neurofilaments during development: A sexual dimorphism.

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