Abstract Background: Patients with actively replicating human immunodeficiency virus (HIV) are highly radiosensitive and exhibit adverse reactions even at low irradiation doses. A major underlying cause is high intra- and extracellular levels of a virus-encoded peptide termed viral protein R (Vpr). As Vpr efficiently crosses the blood-brain barrier and accumulates in astrocytes, we examined whether it may be utilized as a drug in the treatment of glioblastoma multiforme (GBM). Methods: Four glioblastoma-derived cell lines with and without lentivirus-mediated Methylguanine-DNA methyltransferase (MGMT) overexpression (U251, U87, U251-MGMT, U87-MGMT) were exposed to Vpr, temozolomide (TMZ), conventional photon irradiation (2-6 Gy) or to combinations. Caspase assays were employed to detect apoptosis. Colony formation assays were used to analyse clonogenic survival. Dose escalation was performed using n = 12 NOD/SCID/γc−/− (NSG) mice in a classical 3+3 manner. This strain was also used as an orthotopic implant model of glioma using luciferase-expressing U87 cells (n = 18). Continuous Vpr administration was achieved using osmotic pumps, irradiation (3×5 Gy) was performed using a small-animal irradiation device and intracerebral tumor growth was monitored using repetitive contrast-enhanced micro CT scans. Results: Vpr showed high rates of acute toxicities with a LD50 of 4.0±1.1 μM for U251 and a LD50 of 15.7±7.5 μM for U87 cells. Caspase assays revealed Vpr-induced apoptosis in U251 but not in U87 cells. Vpr also efficiently inhibited clonogenic survival both in U251 and U87 cells and showed additive effects with irradiation. In contrast to TMZ, Vpr acted independently of the MGMT expression status. Dose escalation in mice (n = 12) was feasible and resulted in no evident renal or liver toxicity. Similar to irradiation with 3 × 5 Gy (n = 8), Vpr treatment of orthotopically implanted NSG mice (n = 5) delayed tumor growth and significantly (p = 0.041; log-rank test) prolonged overall survival compared to untreated animals (n = 5). Conclusion: The HIV-encoded peptide Vpr exhibits all properties of an effective chemotherapeutic drug and may be a useful agent in the treatment of GBM. Citation Format: Jens Kuebler, Stefanie Kirschner, Linda Hartmann, Grit Welzel, Maren Engelhardt, Carsten Herskind, Marlon R. Veldwijk, Christian Schultz, Manuela Felix, Gerhard Glatting, Patrick Maier, Frederik Wenz, Marc A. Brockmann, Frank A. Giordano. The HIV-derived protein Vpr52-96 has anti-glioma activity in vitro and in vivo. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4458. doi:10.1158/1538-7445.AM2015-4458
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