Molecular mimicry in inducing DNA damage between HIV-1 Vpr and the anticancer agent, cisplatin

Siddiqui, Khwaja M.; Valle, Luis Del; Morellet, Nelly; Cui, Jianqi; Ghafouri, Mohammad; Mukerjee, Ruma; Urbańska, Katarzyna; Fan, Shongshan; Pattillo, Christopher B.; Deshmane, Satish L.; Kiani, Mohammad F.; Ansari, Ramin; Khalili, Kamel; Roques, Bernárd P.; Reiss, Krzysztof; Bouaziz, Serge; Amini, Shohreh; Srinivasan, Alagarsamy; Sawaya, Bassel E.

doi:10.1038/sj.onc.1210632

Cited by 15 publications

(19 citation statements)

References 50 publications

(65 reference statements)

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“…Although the exact mode of action of Vpr is not clarified yet, it has been described that Vpr induces double strand breaks [15,16] causing a cisplatin-and alkylator-like cellular damage signature [15,18]. Here, we also showed that Vpr inhibited clonogenic survival, indicating a considerable genomic damage upon drug exposure.…”

Section: Discussionsupporting

confidence: 64%

“…In addition, Vpr creates cellular damage profiles similar to cisplatin [18] and alkylating agents [15] and the use of the protein as a cancer treatment had been proposed many years ago and the mechanisms behind its effects have been explored since [19]. 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].…”

Section: Research Papermentioning

confidence: 99%

“…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]. The protein was also already employed as a local therapeutic agent by Siddiqui and colleagues, who injected Vpr into mammary carcinoma allografts in mice and observed efficient tumor regression with development of central necrosis in Vpr-treated tumors [18].…”

Section: Research Papermentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 64%

Section: Research Papermentioning

confidence: 99%

Section: Research Papermentioning

confidence: 99%

See 1 more Smart Citation

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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“…As additional peptides were tested which were more carboxy within this region (i.e., peptides P19 and P20), inhibition of tumor cell proliferation was progressively decreased. These results, summarized in Figure 1, indicated that the highest level of inhibition of B16.F10 cell proliferation was mediated by peptide segments spanning amino acids [65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81][82][83]. All of the peptides tested contained a motif, designated H (F/S) RIG, which has been previously identified as mediating the penetration of Vpr into CD4 + lymphocytes with concomitant induction of mitochondrial dysfunction and apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, more recent studies have suggested that other domains of Vpr may molecularly mimic the activity of other established anticancer agents. 70 As such, a more extensive analysis of other regions of Vpr are planned to assess their potential anticancer activity.…”

Section: Discussionmentioning

confidence: 99%

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

Muthumani

Lambert²,

Shanmugam³

et al. 2009

Cancer Biology & Therapy

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Inhibition of NF‐κB activity by HIV‐1 Vpr is dependent on Vpr binding protein

Kogan

Deshmane

Sawaya

et al. 2012

Journal Cellular Physiology

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Numerous studies have reported that Vpr alters NF-κB signaling in various cell types, however, the findings have been largely conflicting with reports of both stimulatory and inhibitory effects of Vpr. Our aim was to investigate the role of Vpr signaling in myeloid cells using an adenovirus based expression and indicator system. Our results show that Vpr is inhibitory to NF-κB, however, this effect is dependant on the particular manner of NF-κB stimulation. Consistent with this notion, we report that Vpr has inhibitory effects that are specific to the TNF-α pathway, but not affecting the LPS pathway, suggesting that differential targets of Vpr may exist for NF-κB regulation. Further, we identify VprBP as one possible cellular component of Vpr’s regulation of IκBα in response to TNF-α stimulation. We did not identify such a role for HSP27, which instead seems to inhibit Vpr functions. Chronically HIV-1 infected U1 cells with knockdown constructs for Vpr were unexpectedly less responsive to TNF-α mediated viral replication, perhaps suggesting that other HIV-1 components may antagonize these anti-NF-κB effects in infected cells. We hypothesize that Vpr may serve an important role in the context of viral infection and immune function in vivo, through its selective inhibition of NF-κB pathways.

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Molecular mimicry in inducing DNA damage between HIV-1 Vpr and the anticancer agent, cisplatin

Cited by 15 publications

References 50 publications

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

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

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

Inhibition of NF‐κB activity by HIV‐1 Vpr is dependent on Vpr binding protein

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