Abstract
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; p3×5 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.
Highlights
Patients infected with the human immunodeficiency virus (HIV) are highly predisposed to develop AIDSdefining and non-AIDS-defining malignancies [1]
U251 and U87 cells were treated with varying concentrations of medium-dissolved viral protein R (Vpr) (0.1 to 20 μM) for 24 to 72 h (Figure 1a and 1b)
Vpr exhibited a concentration-dependent toxicity both in U251 and U87 cells in MTT assays. Both cell lines were susceptible to low doses of Vpr, U251 showed increased sensitivity towards higher doses compared to untreated controls
Summary
Patients infected with the human immunodeficiency virus (HIV) are highly predisposed to develop AIDSdefining and non-AIDS-defining malignancies [1] Many of these tumors (such as Kaposi’s sarcoma or nonHodgkin lymphoma) are highly radiosensitive, radiotherapy (RT) of these tumors may be challenging in HIV-infected patients as they exhibit increased rates of adverse effects even with highly active antiretroviral therapy [2,3,4,5,6]. The agent causing this increase in radiosensitivity is believed to be a virus-encoded peptide termed Viral protein R (Vpr) [7]. Vpr has been found to bind to host cellular DNA, hereby inducing double strand breaks and genomic instability [15, 16], which putatively resembles a conserved mechanism to allow integraseindependent integration of HIV [17]
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