Anti-tumor activity mediated by protein and peptide transduction of HIV viral protein R (Vpr)

Muthumani, Karuppiah; Lambert, Vance M.; Shanmugam, M.; Thieu, Khanh; Choo, Andrew Y.; Chung, Junah; Satishchandran, Abhishek; Kim, J. Joseph; Weiner, David B.; Ugen, Kenneth E.

doi:10.4161/cbt.8.2.7205

Cited by 17 publications

(16 citation statements)

References 58 publications

(88 reference statements)

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“…Earlier studies have shown that it has multiple functions, including induction of G2/M cell cycle arrest and apoptosis in addition to its accessory and regulatory functions as a protein of HIV-1 [5][6][7]. In fact, it has been demonstrated that Vpr renders antiproliferative effects in various types of tumors [8][9][10][11][12]. These results support the hypothesis that Vpr could be used as an antitumor agent in glioma.…”

Section: Introductionsupporting

confidence: 65%

Combined Antitumor Effect of Ad-bFGF-siRNA and Ad-Vpr on the Growth of Xenograft Glioma in Nude Mouse Model

Zhang

Feng

Wang

et al. 2010

Pathol. Oncol. Res.

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Basic fibroblast growth factor (bFGF) has been demonstrated to correlate with glioma grade and clinical outcome and has established its possible usefulness as a target for glioma therapy. Vpr has been described as an antitumor agent and displays a potent antitumor nature. Here, we try to investigate whether a combined treatment with bFGF-siRNA and Vpr gene would have a enhanced effectiveness on glioma in vitro and in vivo.After treatments with only Ad-bFGF-siRNA, only Ad-Vpr, and a combination of both, we assessed the changes in cell proliferation, cell cycle, and apoptosis in vitro by the methods of MTT, PI and FITC-AnnexinV double staining, respectively. In addition, we also evaluated the combined effect of bFGF-siRNA and Vpr gene therapy on glioma in vivo using xenograft glioma models in nude mice. Combined Ad-bFGF-siRNA and Ad-Vpr treatment was more better successful in inhibiting cell proliferation in comparison with treatments of either Ad-bFGF-siRNA or Ad-Vpr alone. Treatment of Ad-Vpr alone or a treatment of a combination of Ad-bFGF-siRNA and Ad-Vpr induced the G2/M cell cycle arrest and apoptosis; however, combined treatment was more effective than the Ad-Vpr treatment alone. Although each single treatment can slow the growth of xenograft glioma, the combined treatment with Ad-bFGF-siRNA and Ad-Vpr was better than either the Ad-bFGF-siRNA or Ad-Vpr treatment alone. Our results suggest that the combination therapy with bFGF-siRNA and Vpr gene can achieve a enhanced activity of anti-glioma, supporting the idea that the combination of these two antitumor agents could open new perspectives in glioma therapy.

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Section: Introductionsupporting

confidence: 65%

Combined Antitumor Effect of Ad-bFGF-siRNA and Ad-Vpr on the Growth of Xenograft Glioma in Nude Mouse Model

Zhang

Feng

Wang

et al. 2010

Pathol. Oncol. Res.

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“…The second prerequisite is also fulfilled by Vpr: several reports have demonstrated that Vpr has proven to be toxic for a variety of tumor cell lines in vitro, including neuroblastoma and grade III astrocytoma cell lines [8,[20][21][22]. For the first time, we here showed that the peptide was not only active in vitro, but also in a murine orthotopic in vivo model.…”

Section: Discussionmentioning

confidence: 55%

“…Various tumor entities are sensitive to Vpr, including neuroblastoma (LAN-2), lymphoma (U937), WHO grade III astrocytoma (U373), cervical cancer (HeLa), liver (HepG2), kidney (293T), melanoma (B16.F10) and leukemia (Jurkat T) cells [8,[20][21][22]. Consequently, first successful approaches to explore the therapeutic efficacy of Vpr were made in gene transfer studies, where Vpr overexpression inhibited growth of melanoma (B78/H1) and oral squamous cell carcinoma cell lines (AT-84) in vitro and in vivo [10,23,24].…”

Section: Research Papermentioning

confidence: 99%

The HIV-Derived Protein Vpr52-96 Has Antiglioma Activity In Vitro and In Vivo

Giordano

Kübler

Kirschner

et al. 2015

International Journal of Radiation Oncology*Biology*Physics

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Patients with actively replicating human immunodeficiency virus (HIV) exhibitadverse 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; p 3x5 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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“…Various tumor entities are sensitive to Vpr, including neuroblastoma (LAN-2), lymphoma (U937), WHO grade III astrocytoma (U373), cervical cancer (HeLa), liver (HepG2), kidney (293T), melanoma (B16.F10) and leukemia (Jurkat T) cells [8, 20–22]. Consequently, first successful approaches to explore the therapeutic efficacy of Vpr were made in gene transfer studies, where Vpr over-expression inhibited growth of melanoma (B78/H1) and oral squamous cell carcinoma cell lines (AT-84) in vitro and in vivo [10, 23, 24].…”

Section: Introductionmentioning

confidence: 99%

The HIV-derived protein Vpr52-96 has anti-glioma activity in vitro and in vivo

et al. 2016

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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.

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Anti-tumor activity mediated by protein and peptide transduction of HIV viral protein R (Vpr)

Cited by 17 publications

References 58 publications

Combined Antitumor Effect of Ad-bFGF-siRNA and Ad-Vpr on the Growth of Xenograft Glioma in Nude Mouse Model

Combined Antitumor Effect of Ad-bFGF-siRNA and Ad-Vpr on the Growth of Xenograft Glioma in Nude Mouse Model

The HIV-Derived Protein Vpr52-96 Has Antiglioma Activity In Vitro and In Vivo

The HIV-derived protein Vpr52-96 has anti-glioma activity in vitro and in vivo

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