Cargando…
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...
Autores principales: | , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1782491971318710272 |
---|---|
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. |
format | Online Article Text |
id | pubmed-5216737 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT kublerjens thehivderivedproteinvpr5296hasantigliomaactivityinvitroandinvivo AT kirschnerstefanie thehivderivedproteinvpr5296hasantigliomaactivityinvitroandinvivo AT hartmannlinda thehivderivedproteinvpr5296hasantigliomaactivityinvitroandinvivo AT welzelgrit thehivderivedproteinvpr5296hasantigliomaactivityinvitroandinvivo AT engelhardtmaren thehivderivedproteinvpr5296hasantigliomaactivityinvitroandinvivo AT herskindcarsten thehivderivedproteinvpr5296hasantigliomaactivityinvitroandinvivo AT veldwijkmarlonr thehivderivedproteinvpr5296hasantigliomaactivityinvitroandinvivo AT schultzchristian thehivderivedproteinvpr5296hasantigliomaactivityinvitroandinvivo AT felixmanuela thehivderivedproteinvpr5296hasantigliomaactivityinvitroandinvivo AT glattinggerhard thehivderivedproteinvpr5296hasantigliomaactivityinvitroandinvivo AT maierpatrick thehivderivedproteinvpr5296hasantigliomaactivityinvitroandinvivo AT wenzfrederik thehivderivedproteinvpr5296hasantigliomaactivityinvitroandinvivo AT brockmannmarca thehivderivedproteinvpr5296hasantigliomaactivityinvitroandinvivo AT giordanofranka thehivderivedproteinvpr5296hasantigliomaactivityinvitroandinvivo AT kublerjens hivderivedproteinvpr5296hasantigliomaactivityinvitroandinvivo AT kirschnerstefanie hivderivedproteinvpr5296hasantigliomaactivityinvitroandinvivo AT hartmannlinda hivderivedproteinvpr5296hasantigliomaactivityinvitroandinvivo AT welzelgrit hivderivedproteinvpr5296hasantigliomaactivityinvitroandinvivo AT engelhardtmaren hivderivedproteinvpr5296hasantigliomaactivityinvitroandinvivo AT herskindcarsten hivderivedproteinvpr5296hasantigliomaactivityinvitroandinvivo AT veldwijkmarlonr hivderivedproteinvpr5296hasantigliomaactivityinvitroandinvivo AT schultzchristian hivderivedproteinvpr5296hasantigliomaactivityinvitroandinvivo AT felixmanuela hivderivedproteinvpr5296hasantigliomaactivityinvitroandinvivo AT glattinggerhard hivderivedproteinvpr5296hasantigliomaactivityinvitroandinvivo AT maierpatrick hivderivedproteinvpr5296hasantigliomaactivityinvitroandinvivo AT wenzfrederik hivderivedproteinvpr5296hasantigliomaactivityinvitroandinvivo AT brockmannmarca hivderivedproteinvpr5296hasantigliomaactivityinvitroandinvivo AT giordanofranka hivderivedproteinvpr5296hasantigliomaactivityinvitroandinvivo |