Endostatin-Cytosine Deaminase Fusion Protein Suppresses Tumor Growth by Targeting Neovascular Endothelial Cells

Ou‐Yang, Fu; Lan, Keng Li; Chen, Chun‐Te; Liu, Jaw Ching; Weng, Chu Li; Chou, Chao-Kai; Xie, Xiaoming; Hung, Jen Yu; Wei, Yongkun; Hortobágyi, Gabriel N.; Hung, Mien Chie

doi:10.1158/0008-5472.can-05-1578

Cited by 16 publications

(12 citation statements)

References 17 publications

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“…In vitro tube formation assay To evaluate the antiangiogenic activity of PEDF produced by hMSCs-PEDF, an in vitro tube formation assay was performed as described previously (Ou-Yang et al, 2006). Matrigel (50 ml; BD Biosciences, San Jose, CA, USA) was added to each well of a 96-well plate and allowed to polymerize.…”

Section: Western Blotmentioning

confidence: 99%

Human mesenchymal stem cells overexpressing pigment epithelium-derived factor inhibit hepatocellular carcinoma in nude mice

et al. 2010

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The poor outcome of cancer gene therapy in clinical trials relates in part to insufficient gene delivery to tumor sites. Mesenchymal stem cells (MSCs) represent a new tool for the delivery of therapeutic agents to tumor cells. This study used an orthotopic nude mice model of hepatocellular carcinoma (HCC) to evaluate the potential of genetically modified human MSCs (hMSCs), to function as an effective delivery vehicle for therapeutic genes. hMSCs derived from the bone marrow were efficiently engineered to express human pigment epithelium-derived factor (PEDF) by lentiviral transduction, then tested in vitro for high-level expression and bioactivity of the transgenic protein. The preferential homing of hMSCs toward HCC was confirmed by in vitro and in vivo migration assays. in vivo efficacy experiments showed that intravenous (i.v.) injection of PEDF-expressing hMSCs significantly suppressed both the growth of primary liver tumors and the development of pulmonary metastases. Moreover, hMSCs-based PEDF gene delivery moderately increased the systemic levels of human PEDF. Immunohistochemistry of primary liver tumors demonstrated lower microvessel density in mice treated with hMSCs-PEDF than in control mice. This is the first study to show the potential of hMSCs as an effective delivery vehicle for therapeutic genes in the treatment of HCC.

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Section: Western Blotmentioning

confidence: 99%

Human mesenchymal stem cells overexpressing pigment epithelium-derived factor inhibit hepatocellular carcinoma in nude mice

et al. 2010

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“…Tube formation assay was done as previously described (2). In brief, 3 × 10 4 endothelial cells were seeded on a layer of polymerized Matrigel (BD Biosciences) in a 96-well plate.…”

Section: Translational Relevancementioning

confidence: 99%

“…Apart from angiogenesis inhibitors, so-called vascular disrupting agents targeted at the established tumor vasculature are currently being investigated in clinical trial. Recently, we revealed that an endostatin-cytosine deaminase fusion protein possesses the tumor vessel-targeting property of endostatin to allow selective tumor-killing effect of cytosine deaminase, producing potent antitumor activity (2).…”

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confidence: 99%

EPOX Inhibits Angiogenesis by Degradation of Mcl-1 through ERK Inactivation

Sun

Tsai

Pan

et al. 2009

Clinical Cancer Research

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Purpose: Antiangiogenic therapy is considered as an effective strategy for controlling the growth and metastasis of tumors. Among a myriad of biological activities described for xanthone derivatives, the anticancer activity is quite remarkable, but the molecular mechanism is not clearly resolved. In the present study, we investigated the antiangiogenic mechanism of 3,6-di(2,3-epoxypropoxy)xanthone (EPOX), a novel Mcl-1 targeting drug. Experimental Design: To evaluate the antiangiogenic activity of EPOX, we did cell viability, cell cycle, tube formation assay in vitro, and Matrigel plug assay in vivo. To evaluate the effect of EPOX on the endothelial signaling pathway, we did immunoblotting, immunoprecipitation, and immunofluorescence analysis. Intracellular glutathione levels were determined with the use of monochlorobimane, a glutathione-specific probe. Results: EPOX induced endothelial cell apoptosis in association with proteasomedependent Mcl-1 degradation. Down-regulation of Mcl-1 resulted in an increase in Mcl-1-free Bim, activation of Bax, and then signaling of mitochondria-mediated apoptosis. Additionally, glutathione depletion and extracellular signal-regulated kinase (ERK) inactivation was observed in EPOX-treated cells. Glutathione supplementation reversed the inhibitory effects of EPOX on ERK, which increases the phosphorylation of Mcl-1 at T 163 . Overexpression of mitogen-activated protein/ERK kinase (MEK) partially reversed the effect of EPOX on Mcl-1 dephosphorylation, ubiquitination, and degradation, further implicating ERK in the regulation of Mcl-1 stability. Conclusions: This study provides evidence that EPOX induces glutathione depletion, ERK inactivation, and Mcl-1 degradation on endothelial cells, which leads to inhibition of angiogenesis. Our results suggest that EPOX is a novel antiangiogenic agent, making it a promising lead compound for further development in the treatment of angiogenesisrelated pathologies.

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“…The EZC-prostate model in which prostate cancer cell lines (LNCaP-Luc and PC-3-Luc) stably expressing firefly luciferase enzyme facilitated live imaging of established orthotopic prostate cancer xenografts (25, 29) and enabled real-time monitoring of prostate tumor growth and metastases without having to sacrifice the animals. An orthotopic model by injecting tumor cells into the prostate better mimics the prostate cancer in clinics than a subcutaneous model.…”

Section: Discussionmentioning

confidence: 99%

Targeted BikDD Expression Kills Androgen-Dependent and Castration-Resistant Prostate Cancer Cells

Xie

Kong

Tang

et al. 2014

Molecular Cancer Therapeutics

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Targeted gene therapy is a promising approach for treating prostate cancer after the discovery of prostate cancer-specific promoters such as prostate-specific antigen, rat probasin, and human glandular kallikrein. However, these promoters are androgen-dependent, and after castration or androgen ablation therapy, they become much less active or sometimes inactive. Importantly, the disease will inevitably progress from androgen-dependent (ADPC) to castration-resistant prostate cancer (CRPC) at which treatments fail and high mortality ensues. Therefore, it is critical to develop a targeted gene therapy strategy that is effective in both ADPC and CRPC to eradicate recurrent prostate tumors. The human telomerase reverse transcriptase-VP16-Gal4-WPRE integrated systemic amplifier composite (T-VISA) vector we previously developed which targets transgene expression in ovarian and breast cancer is also active in prostate cancer. To further improve its effectiveness based on androgen response in ADPC progression, the ARR2 element (two copies of androgen response region from rat probasin promoter) was incorporated into T-VISA to produce AT-VISA. Under androgen analog (R1881) stimulation, the activity of AT-VISA was increased to a level greater than or comparable to the cytomegalovirus (CMV) promoter in ADPC and CRPC cells, respectively. Importantly, AT-VISA demonstrated little or no expression in normal cells. Systemic administration of AT-VISA-BikDD encapsulated in liposomes repressed prostate tumor growth and prolonged mouse survival in orthotopic animal models as well as in the transgenic adenocarcinoma mouse prostate model, indicating that AT-VISA-BikDD has therapeutic potential to treat ADPC and CRPC safely and effectively in preclinical setting.

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Endostatin-Cytosine Deaminase Fusion Protein Suppresses Tumor Growth by Targeting Neovascular Endothelial Cells

Cited by 16 publications

References 17 publications

Human mesenchymal stem cells overexpressing pigment epithelium-derived factor inhibit hepatocellular carcinoma in nude mice

Human mesenchymal stem cells overexpressing pigment epithelium-derived factor inhibit hepatocellular carcinoma in nude mice

EPOX Inhibits Angiogenesis by Degradation of Mcl-1 through ERK Inactivation

Targeted BikDD Expression Kills Androgen-Dependent and Castration-Resistant Prostate Cancer Cells

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