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The HIV-derived protein Vpr(52-96) has anti-glioma activity in vitro and in vivo

Patients with actively replicating human immunodeficiency virus (HIV) exhibit adverse reactions even to low irradiation doses. High levels of the virus-encoded viral protein R (Vpr) are believed to be one of the major underlying causes for increased radiosensitivity. As Vpr efficiently crosses the b...

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Autores principales: Kübler, Jens, Kirschner, Stefanie, Hartmann, Linda, Welzel, Grit, Engelhardt, Maren, Herskind, Carsten, Veldwijk, Marlon R., Schultz, Christian, Felix, Manuela, Glatting, Gerhard, Maier, Patrick, Wenz, Frederik, Brockmann, Marc A., Giordano, Frank A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5216737/
https://www.ncbi.nlm.nih.gov/pubmed/27275537
http://dx.doi.org/10.18632/oncotarget.9787
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author Kübler, Jens
Kirschner, Stefanie
Hartmann, Linda
Welzel, Grit
Engelhardt, Maren
Herskind, Carsten
Veldwijk, Marlon R.
Schultz, Christian
Felix, Manuela
Glatting, Gerhard
Maier, Patrick
Wenz, Frederik
Brockmann, Marc A.
Giordano, Frank A.
author_facet Kübler, Jens
Kirschner, Stefanie
Hartmann, Linda
Welzel, Grit
Engelhardt, Maren
Herskind, Carsten
Veldwijk, Marlon R.
Schultz, Christian
Felix, Manuela
Glatting, Gerhard
Maier, Patrick
Wenz, Frederik
Brockmann, Marc A.
Giordano, Frank A.
author_sort Kübler, Jens
collection PubMed
description Patients with actively replicating human immunodeficiency virus (HIV) exhibit adverse reactions even to low irradiation doses. High levels of the virus-encoded viral protein R (Vpr) are believed to be one of the major underlying causes for increased radiosensitivity. As Vpr efficiently crosses the blood-brain barrier and accumulates in astrocytes, we examined its efficacy as a drug for treatment of glioblastoma multiforme (GBM). In vitro, four glioblastoma-derived cell lines with and without methylguanine-DNA methyltransferase (MGMT) overexpression (U251, U87, U251-MGMT, U87-MGMT) were exposed to Vpr, temozolomide (TMZ), conventional photon irradiation (2 to 6 Gy) or to combinations thereof. Vpr showed high rates of acute toxicities with median effective doses of 4.0±1.1 μM and 15.7±7.5 μM for U251 and U87 cells, respectively. Caspase assays revealed Vpr-induced apoptosis in U251, but not in U87 cells. Vpr also efficiently inhibited clonogenic survival in both U251 and U87 cells and acted additively with irradiation. In contrast to TMZ, Vpr acted independently of MGMT expression. Dose escalation in mice (n=12) was feasible and resulted in no evident renal or liver toxicity. Both, irradiation with 3×5 Gy (n=8) and treatment with Vpr (n=5) delayed intracerebral tumor growth and prolonged overall survival compared to untreated animals (n=5; p(3×5 Gy)<0.001 and p(Vpr)=0.04; log-rank test). Our data show that the HIV-encoded peptide Vpr exhibits all properties of an effective chemotherapeutic drug and may be a useful agent in the treatment of GBM.
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spelling pubmed-52167372017-01-15 The HIV-derived protein Vpr(52-96) has anti-glioma activity in vitro and in vivo Kübler, Jens Kirschner, Stefanie Hartmann, Linda Welzel, Grit Engelhardt, Maren Herskind, Carsten Veldwijk, Marlon R. Schultz, Christian Felix, Manuela Glatting, Gerhard Maier, Patrick Wenz, Frederik Brockmann, Marc A. Giordano, Frank A. Oncotarget Research Paper Patients with actively replicating human immunodeficiency virus (HIV) exhibit adverse reactions even to low irradiation doses. High levels of the virus-encoded viral protein R (Vpr) are believed to be one of the major underlying causes for increased radiosensitivity. As Vpr efficiently crosses the blood-brain barrier and accumulates in astrocytes, we examined its efficacy as a drug for treatment of glioblastoma multiforme (GBM). In vitro, four glioblastoma-derived cell lines with and without methylguanine-DNA methyltransferase (MGMT) overexpression (U251, U87, U251-MGMT, U87-MGMT) were exposed to Vpr, temozolomide (TMZ), conventional photon irradiation (2 to 6 Gy) or to combinations thereof. Vpr showed high rates of acute toxicities with median effective doses of 4.0±1.1 μM and 15.7±7.5 μM for U251 and U87 cells, respectively. Caspase assays revealed Vpr-induced apoptosis in U251, but not in U87 cells. Vpr also efficiently inhibited clonogenic survival in both U251 and U87 cells and acted additively with irradiation. In contrast to TMZ, Vpr acted independently of MGMT expression. Dose escalation in mice (n=12) was feasible and resulted in no evident renal or liver toxicity. Both, irradiation with 3×5 Gy (n=8) and treatment with Vpr (n=5) delayed intracerebral tumor growth and prolonged overall survival compared to untreated animals (n=5; p(3×5 Gy)<0.001 and p(Vpr)=0.04; log-rank test). Our data show that the HIV-encoded peptide Vpr exhibits all properties of an effective chemotherapeutic drug and may be a useful agent in the treatment of GBM. Impact Journals LLC 2016-06-02 /pmc/articles/PMC5216737/ /pubmed/27275537 http://dx.doi.org/10.18632/oncotarget.9787 Text en Copyright: © 2016 Kübler et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Kübler, Jens
Kirschner, Stefanie
Hartmann, Linda
Welzel, Grit
Engelhardt, Maren
Herskind, Carsten
Veldwijk, Marlon R.
Schultz, Christian
Felix, Manuela
Glatting, Gerhard
Maier, Patrick
Wenz, Frederik
Brockmann, Marc A.
Giordano, Frank A.
The HIV-derived protein Vpr(52-96) has anti-glioma activity in vitro and in vivo
title The HIV-derived protein Vpr(52-96) has anti-glioma activity in vitro and in vivo
title_full The HIV-derived protein Vpr(52-96) has anti-glioma activity in vitro and in vivo
title_fullStr The HIV-derived protein Vpr(52-96) has anti-glioma activity in vitro and in vivo
title_full_unstemmed The HIV-derived protein Vpr(52-96) has anti-glioma activity in vitro and in vivo
title_short The HIV-derived protein Vpr(52-96) has anti-glioma activity in vitro and in vivo
title_sort hiv-derived protein vpr(52-96) has anti-glioma activity in vitro and in vivo
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5216737/
https://www.ncbi.nlm.nih.gov/pubmed/27275537
http://dx.doi.org/10.18632/oncotarget.9787
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