Dataset Information

A New Patient-Derived Metastatic Glioblastoma Cell Line: Characterisation and Response to Sodium Selenite Anticancer Agent.

ABSTRACT: Glioblastoma multiform (GBM) tumors are very heterogeneous, organized in a hierarchical pattern, including cancer stem cells (CSC), and are responsible for development, maintenance, and cancer relapse. Therefore, it is relevant to establish new GBM cell lines with CSC characteristics to develop new treatments. A new human GBM cell line, named R2J, was established from the cerebro-spinal fluid (CSF) of a patient affected by GBM with leptomeningeal metastasis. R2J cells exhibits an abnormal karyotype and form self-renewable spheres in a serum-free medium. Original tumor, R2J, cultured in monolayer (2D) and in spheres showed a persistence expression of CD44, CD56 (except in monolayer), EGFR, Ki67, Nestin, and vimentin. The R2J cell line is tumorigenic and possesses CSC properties. We tested in vitro the anticancer effects of sodium selenite (SS) compared to temozolomide TMZ. SS was absorbed by R2J cells, was cytotoxic, induced an oxidative stress, and arrested cell growth in G2M before inducing both necrosis and apoptosis via caspase-3. SS also modified dimethyl-histone-3-lysine-9 (H3K9m2) levels and decreased histone deacetylase (HDAC) activity, suggesting anti-invasiveness potential. This study highlights the value of this new GBM cell line for preclinical modeling of clinically relevant, patient specific GBM and opens a therapeutic window to test SS to target resistant and recurrent GBM.

SUBMITTER: Berthier S

PROVIDER: S-EPMC6356827 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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A New Patient-Derived Metastatic Glioblastoma Cell Line: Characterisation and Response to Sodium Selenite Anticancer Agent.

Berthier Sylvie S Larrouquère Louis L Champelovier Pierre P Col Edwige E Lefebvre Christine C Cottet-Rouselle Cécile C Arnaud Josiane J Garrel Catherine C Laporte François F Boutonnat Jean J Faure Patrice P Hazane-Puch Florence F

Cancers 20181221 1

Glioblastoma multiform (GBM) tumors are very heterogeneous, organized in a hierarchical pattern, including cancer stem cells (CSC), and are responsible for development, maintenance, and cancer relapse. Therefore, it is relevant to establish new GBM cell lines with CSC characteristics to develop new treatments. A new human GBM cell line, named R2J, was established from the cerebro-spinal fluid (CSF) of a patient affected by GBM with leptomeningeal metastasis. R2J cells exhibits an abnormal karyot ...[more]

PMID: 30583471

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Project description:BackgroundSelenite is a radiosensitizer and inhibitor of androgen receptor expression and function. In a phase I study (NCT02184533) in 15 subjects with metastatic cancer receiving daily oral sodium selenite with palliative radiation therapy, disease stabilization was observed, as evidenced by tumor regression, marked reduction in pain symptoms, and decreased prostate-specific antigen levels (only patients with castrate-resistant prostate cancer).ObjectiveThe aim of this work was to characterize the pharmacokinetics of selenite to suggest dosing strategies and to propose a study design for further investigation.MethodsWith selenium plasma concentrations obtained from five dosing cohorts (5.5, 11, 16.5, 33, and 49.5 mg), a population pharmacokinetic model was constructed using NONMEM. The model described externally administered selenite (inorganic) with a baseline component for endogenous selenium levels. Using the pharmacokinetic model, simulations were performed to suggest dosing regimens that achieved in vitro target selenite levels, and optimal pharmacokinetic sampling times for a subsequent study were proposed using PopED.ResultsA one-compartment model characterized selenite pharmacokinetics. Parameter estimates were absorption rate constant (0.64 h-1), apparent clearance (1.58 L/h), apparent volume of distribution (42.3 L), and baseline selenium amount (5270 μg). A logarithmic function characterized the inverse relationship between dose level and bioavailability. Four regimens to reach in vitro target selenite levels were proposed: 33 mg daily, 16.5 mg twice daily (BID), 11 mg BID, and 5.5 mg thrice daily (TID). Optimal sampling times were 1, 2, 6, and 24 h.DiscussionThe population model described the pharmacokinetic data well. Three regimens (33 mg daily, 11 mg BID, 5.5 mg TID) achieved in vitro target selenite levels after one dose. The model and optimal sampling times may inform future studies evaluating the efficacy of selenite for metastatic cancer treatment.

Dataset Information

A New Patient-Derived Metastatic Glioblastoma Cell Line: Characterisation and Response to Sodium Selenite Anticancer Agent.

Publications

A New Patient-Derived Metastatic Glioblastoma Cell Line: Characterisation and Response to Sodium Selenite Anticancer Agent.

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