The HIV-derived protein Vpr52-96 has anti-glioma activity in vitro and in vivo
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Jens Kübler1,*, Stefanie Kirschner2,*, Linda Hartmann1, Grit Welzel1, Maren Engelhardt3, Carsten Herskind1, Marlon R. Veldwijk1, Christian Schultz3, Manuela Felix4, Gerhard Glatting4, Patrick Maier1, Frederik Wenz1, Marc A. Brockmann5,*, Frank A. Giordano1,*
1Department of Radiation Oncology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
2Department of Neuroradiology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
3Centre for Biomedicine and Medical Technology Mannheim (CBTM), Institute of Neuroanatomy, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
4Medical Radiation Physics/Radiation Protection, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
5Department of Neuroradiology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
*These authors have contributed equally to this work
Frank A. Giordano, email: [email protected]
Keywords: glioblastoma, viral protein R, irradiation, MGMT, temozolomide
Received: February 06, 2016 Accepted: May 16, 2016 Published: June 2, 2016
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 3x5 Gy (n=8) and treatment with Vpr (n=5) delayed intracerebral tumor growth and prolonged overall survival compared to untreated animals (n=5; p3x5 Gy<0.001 and pVpr=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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