The human immunodeficiency virus type 1 Vpr protein and its carboxy-terminally truncated form induce apoptosis in tumor cells

Nonaka, Mizuho; Hashimoto, Yoshie; Takeshima, Shin‐nosuke; Aida, Yoko

doi:10.1186/1475-2867-9-20

Cited by 17 publications

(13 citation statements)

References 46 publications

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“…HIV-Tat may be a useful platform for future investigations into MOMP/PTP independent targeting of malignant mitochondria. The toxic consequences of HIV-Tat are related to another mitochondriotoxic HIV protein (HIV-1 viral protein R or VpR; Table 1 ), which has been used to target the mitochondria of cancer cells [44]. …”

Section: Malignant Mitochondria (The Tumor Signature)mentioning

confidence: 99%

Targeting Malignant Mitochondria With Therapeutic Peptides

Constance

Lim

2012

Therapeutic Delivery

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The current status of peptides that target the mitochondria in the context of cancer is the focus of this review. Chemotherapy and radiotherapy used to kill tumor cells are principally mediated by the process of apoptosis that is governed by the mitochondria. The failure of anticancer therapy often resides at the level of the mitochondria. Therefore, the mitochondrion is a key pharmacological target in cancer due to many of the differences that arise between malignant and healthy cells at the level of this ubiquitous organelle. Additionally, targeting the characteristics of malignant mitochondria often rely on disruption of protein-protein interactions that are not generally amenable to small molecules. We discuss anticancer peptides that intersect with pathological changes in the mitochondrion.The mitochondrion holds importance among cellular organelles in consideration of selective anticancer therapy because it is the nexus for propagating malignant transformation and controls cell death. The mitochondrion is a universal target in all cancer cells, and new information about functional and structural differences between healthy and malignant cells continues to emerge [1]. Peptides that specifically target malignant mitochondria offer advantages of low toxicity, high specificity and generally increase the range of interactions that are difficult to target with small molecules (e.g., protein-protein, protein-lipid and protein-DNA) [2]. However, the benefits of peptides are offset by difficulties in delivery, such as degradation by proteases and rapid clearance. As such, the delivery of peptide/ protein therapeutics is almost exclusively by the parenteral route, but the status quo is actively being challenged by broad efforts (e.g., liposomes, microparticles, nanoparticles, 'smart' polymers, hydrogels and chemical modifications to the peptide/protein) to achieve more convenient routes of administration (i.e., oral, nasal and transdermal) and improved pharmacokinetics [3][4][5]. However, peptides, in many cases, are far from passive in the delivery process and through the maze that is drug delivery (from route of administration to perhaps a target residing within a specific organelle), peptides are employed as the vehicle, homing motif and trans-/intra-cellular passport [6].There is an emerging view in cancer therapy that the way in which a cancer cell dies (i.e., immunogenic cell death) is important for a durable response [7]. However, traditional chemo therapy and immune response are in conflict because chemotherapy (e.g., DNA-© 2012 Future Science Ltd * Author for correspondence: Tel.: +1 801 581 7120 Fax: +1 801 585 3614 carol.lim@pharm.utah.edu. Financial & competing interests disclosureThe authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript....

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Section: Malignant Mitochondria (The Tumor Signature)mentioning

confidence: 99%

Targeting Malignant Mitochondria With Therapeutic Peptides

Constance

Lim

2012

Therapeutic Delivery

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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: 56%

“…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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“…We also assessed cell cycle distribution in these cells because Vpr-mediated cell cycle arrest appears to be dependent on the cell type (11). We found that 48 h after infection, Ad-Vpr led to a significant increase in the proportion of hyperploid (>4n) cells (39.97±1.88%) compared to the control (10.0±3.24%, p<0.05) or Ad-GFP infected cells (9.66±3.51%, p<0.05) (Fig.…”

Section: Ad-vpr Infection Induces Cell Cycle Arrest At G2/m and Apoptmentioning

confidence: 99%

“…Expression of Vpr protein was able to induce cell cycle arrest and apoptosis. Therefore, many studies have analyzed the potential antitumor activity of this molecule both in vitro and in vivo (7)(8)(9)(10)(11)(12)(13)(14)(15). Previous studies have shown that the Vpr protein appears to preferentially inhibit the growth of rapidly dividing tumor cells, but does not affect the normal cells regardless of changes in p53 expression (7)(8)(9)15 Abbreviations: Ad, adenovirus; GFP, green fluorescent protein; Vpr, viral protein R; MOI, multiplicity of infection; MTT, 3-(4,5)-dimethylthiazo(-2-yl)-2,5-di-phenyltetrazolium bromide; PI, propidium iodide; NF-κB, nuclear factor-κB…”

Section: Introductionmentioning

confidence: 99%

HIV-1 viral protein R (Vpr) induction of apoptosis and cell cycle arrest in multidrug-resistant colorectal cancer cells

Zhang

Wang

et al. 2012

Oncol Rep

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Abstract. Colorectal cancer is a significant health problem, and the advanced stages of the disease have a low response rate to chemotherapy and easily acquire chemoresistance. HIV-1 viral protein R (Vpr) has been shown to possess inhibitory effects on various malignant cells in vivo and in vitro. In this study, an Ad-Vpr construct was used to infect the multidrug-resistant human colorectal cancer HCT-8/5-FU(MDR) cell line in vitro for cell viability, apoptosis, gene expression and gene activity using the MTT, flow cytometry, immunoblotting and gel shift assays, respectively. The data showed that Ad-Vpr significantly reduced HCT-8/5-FU(MDR) cell viability in a dose-and time-dependent manner. Ad-Vpr infection promoted HCT-8/5-FU(MDR) cells to undergo apoptosis and to arrest at the G2 phase of the cell cycle. The G2 cell cycle protein Cyclin B1 accumulated in the cells after Ad-Vpr infection. Furthermore, Ad-Vpr induced activation of caspase-3 and -9, but not caspase-8, in HCT-8/5-FU(MDR) cells. Ad-Vpr suppressed expression of the Bcl-xl protein, but upregulated Bax expression and cytochrome c release from the mitochondria in HCT-8/5-FU(MDR) cells. Ad-Vpr infection also resulted in a time-dependent decrease in nuclear translocation of NF-κB/p65 protein and p65 DNA-binding activity in HCT-8/5-FU(MDR) cells. The data from the current study provide mechanistic insights into understanding the molecular basis and utility of Ad-Vpr as a novel anticancer agent for multidrug resistance in human colorectal cancer. IntroductionColorectal cancer is a significant health problem in the world, and is the third most common cancer in women and the fourth most common in men. More than half a million patients with colorectal cancer die of the disease annually worldwide (1,2). To date, surgical intervention is the most effective tool to cure colorectal cancer, whereas chemotherapy is another important means to treat colorectal cancer, especially for advanced staged disease. In those patients, chemotherapy appears to be the only therapeutic modality and offers some benefit. For chemotherapy, 5-fluorouracil (5-FU)-based regimens are the most common choice for patients. The combination of 5-FU with irinotecan and oxaliplatin has significantly improved the response rate of colorectal cancer patients. Additionally, combination regimens of 5-FU with irinotecan have been evaluated as the first-line therapeutic selection for advanced colorectal cancer with a response rate of 30-50% and an overall survival of 14-20 months (3,4). However, the response rate for these advanced targeted therapies and third-generation chemotherapies remains low (5). The reason may be due to innate and acquired chemoresistance (6) of colorectal cancer, which often leads to relapse and poor patient prognosis. Thus, a more aggressive and effective therapy to control colorectal cancer is imperative.To this end, our research focuses on the viral protein R (Vpr), which is an accessory protein and plays an important role in the regulation of nuclear import of the HIV-1 ...

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The human immunodeficiency virus type 1 Vpr protein and its carboxy-terminally truncated form induce apoptosis in tumor cells

Cited by 17 publications

References 46 publications

Targeting Malignant Mitochondria With Therapeutic Peptides

Targeting Malignant Mitochondria With Therapeutic Peptides

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

HIV-1 viral protein R (Vpr) induction of apoptosis and cell cycle arrest in multidrug-resistant colorectal cancer cells

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