scholarly journals Inhibition of breast cancer cells by targeting E2F-1 gene and expressing IL15 oncolytic adenovirus

2019 ◽  
Vol 39 (7) ◽  
Author(s):  
Yang Yan ◽  
Hu Xu ◽  
Jiandong Wang ◽  
Xin Wu ◽  
Wei Wen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Therapy ◽  
Recombinant Adenovirus ◽  
Oncolytic Adenovirus ◽  
The Novel ◽  
Gene Therapy Application ◽  
Interleukin 15 ◽  
Breast Cancer Virus

Abstract The wide application of oncolytic adenovirus presents a novel therapeutic strategy for breast cancer gene therapy. Application of adenovirus alone achieves little curative effects on breast cancer. In addition, it is worth exploring the synergistic anti-tumor effect by inserting immunomodulatory factor in oncolytic adenovirus genome. By taking the advantage of the highly proliferative property of breast cancer, a novel recombinant adenovirus which could selectively kill tumor cells is established under an E2F-1 promoter. Also by carrying human Interleukin-15 (IL-15) gene, the oncolytic adenovirus exhibits an immunomodulatory effect. The present study proved that the novel oncolytic virus (SG400-E2F/IL-15) exhibits an enhanced anti-tumor activity both in vitro and in vivo, representing an experimental basis for breast cancer “virus-gene” therapy.

Abstract 229: The Novel Angiogenic Cytokine Secretoneurin promotes Angiogenesis, Arteriogenesis and Vasculogenesis in the Hind-Limb Ischemia Model

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Wilfried Schgoer ◽  
Margot Egger ◽  
Arno Peer ◽  
Johannes Jeschke ◽  
Ivan Tancevski ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Bone Marrow ◽  
Green Fluorescence Protein ◽  
Limb Ischemia ◽  
Promoter Sequence ◽  
The Novel ◽  
Gene Therapy Vector ◽  
Adductor Muscles

Introduction - Secretoneurin (SN) represents a sensory, inflammatory neuropeptide which was recently demonstrated to act as an angiogenic and vasculogenic cytokine in vitro and in vivo. The present study was conducted to test the hypothesis that SN may be implicated in reparative angiogenesis. Furthermore, we challenged the healing potential of SN applied as a newly generated SN gene therapy vector in the setting of limb ischemia. Methods and Results - We cloned the human SN coding sequence into the pAAV plasmid containing a cytomegalovirus enhancer/promoter sequence. Bioactivity of recombinant SN was shown by proliferative and chemotactic activity on endothelial cells in vitro. Unilateral limb ischemia was induced in C57/bl mice by femoral artery resection. By Real Time PCR, Western Blotting, SN-specific RIA and Immunhistochemistry, we documented that SN is up-regulated in ischemic muscles. Next, we tested whether SN gene therapy may exert curative effects in this ischemia model. Injection of the SN plasmid into ischemic adductor muscles increased capillary (0.67 vs. 0.35, n = 24, p = 0.02) and arteriole (0.16 vs. 0.8, n = 24, p = 0.04) density, reduced endothelial cell apoptosis, and accelerated perfusion recovery as shown by Laser Doppler Perfusion Index (LDPI ratio ischemic/control leg after 28 days of ischemia 1.1 vs. 0.7, n = 24, p < 0.01) in comparson to pAAV-GFP (green-fluorescence protein) treated mice. Furthermore, SN gene therapy significantly reduced toe necrosis of ischemic limbs compared to control animals (26% vs. 50%, n = 24, p < 0.05). In bone marrow transplantation models, increased vascularity of ischemic hind-limbs after SN gene therapy was shown to be mediated, at least in part, by enhanced recruitment of bone marrow-derived endothelial progenitor cells. Conclusions -These results suggest that the novel angiogenic cytokine Secretoneurin is up-regulated by ischemia in skeletal muscle cells. Furthermore, results from gene therapy in this ischemia model suggest that Secretoneurin represent a promising new substance for therapeutic angiogenesis.

scholarly journals Oncolytic adenovirus armed with IL-24 Inhibits the growth of breast cancer in vitro and in vivo

2012 ◽  
Vol 31 (1) ◽  
pp. 51 ◽  
Author(s):  
Wei Zhu ◽  
Lai Wei ◽  
Hongwei Zhang ◽  
Junxue Chen ◽  
Xinyu Qin
Keyword(s):  
Breast Cancer ◽  
Oncolytic Adenovirus

scholarly journals Adenovirus-Mediated Expression of a Ribozyme to c-mybmRNA Inhibits Smooth Muscle Cell Proliferation and Neointima Formation In Vivo

1999 ◽  
Vol 73 (9) ◽  
pp. 7745-7751 ◽  
Author(s):  
Dennis G. Macejak ◽  
Hua Lin ◽  
Saiphone Webb ◽  
Jennifer Chase ◽  
Kristi Jensen ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Smooth Muscle ◽  
Animal Models ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Recombinant Adenovirus ◽  
Neointima Formation ◽  
Inhibition Of Proliferation

ABSTRACT Smooth muscle cell (SMC) proliferation is an important component of restenosis in response to injury after balloon angioplasty. Inhibition of proliferation in vivo can limit neointima hyperplasia in animal models of restenosis. Ribozymes against c-myb mRNA have been shown to be effective inhibitors of SMC proliferation in vitro. The effectiveness of adenovirus as a gene therapy vector in animal models of restenosis is well documented. In order to test the utility of ribozymes to inhibit SMC proliferation by a gene therapy approach, recombinant adenovirus expressing ribozymes against c-mybmRNA was generated and tested both in vitro and in vivo. This adenovirus ribozyme vector is shown to inhibit SMC proliferation in culture and neointima formation in a rat carotid artery balloon injury model of restenosis.

scholarly journals Combination Therapy of Novel Oncolytic Adenovirus with Anti-PD1 Resulted in Enhanced Anti-Cancer Effect in Syngeneic Immunocompetent Melanoma Mouse Model

Pharmaceutics ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 547
Author(s):  
Mariangela Garofalo ◽  
Laura Bertinato ◽  
Monika Staniszewska ◽  
Magdalena Wieczorek ◽  
Stefano Salmaso ◽  
...  
Keyword(s):  
Mouse Model ◽  
Enzyme Assay ◽  
Survival Rates ◽  
Oncolytic Adenovirus ◽  
The Novel ◽  
Anti Cancer ◽  
Check Point Inhibitors ◽  
Melanoma Therapy

Malignant melanoma, an aggressive form of skin cancer, has a low five-year survival rate in patients with advanced disease. Immunotherapy represents a promising approach to improve survival rates among patients at advanced stage. Herein, the aim of the study was to design and produce, by using engineering tools, a novel oncolytic adenovirus AdV-D24- inducible co-stimulator ligand (ICOSL)-CD40L expressing potent co-stimulatory molecules enhancing clinical efficacy through the modulation of anti-cancer immune responses. Firstly, we demonstrated the vector’s identity and genetic stability by restriction enzyme assay and sequencing, then, by performing in vitro and in vivo pre-clinical studies we explored the anti-cancer efficacy of the virus alone or in combination with anti PD-1 inhibitor in human melanoma cell lines, i.e., MUG Mel-1 and MUG Mel-2, and in immunocompetent C57BL/6 melanoma B16V mouse model. We showed that both monotherapy and combination approaches exhibit enhanced anti-cancer ability and immunogenic cell death in in vitro settings. Furthermore, AdV-D24-ICOSL-CD40L combined with anti PD-1 revealed a fall in tumor volume and 100% survival in in vivo context, thus suggesting enhanced efficacy and survival via complementary anti-cancer properties of those agents in melanoma therapy. Collectively, the novel oncolytic vector AdV-D24-ICOSL-CD40L alone or in combination with anticancer drugs, such as check point inhibitors, may open novel therapeutic perspectives for the treatment of melanoma.

scholarly journals The Efficiency of Gene Electrotransfer in Breast-Cancer Cell Lines Cultured on a Novel Collagen-Free 3D Scaffold

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 1043 ◽  
Author(s):  
Elisabetta Sieni ◽  
Monica Dettin ◽  
Mariangela De Robertis ◽  
Bianca Bazzolo ◽  
Maria Teresa Conconi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Breast Cancer Cell ◽  
Cell Cultures ◽  
Transfection Efficiency ◽  
Breast Cancer Cell Lines ◽  
The Novel ◽  
3D Scaffold

Gene Electro-Transfer (GET) is a powerful method of DNA delivery with great potential for medical applications. Although GET has been extensively studied in vitro and in vivo, the optimal parameters remain controversial. 2D cell cultures have been widely used to investigate GET protocols, but have intrinsic limitations, whereas 3D cultures may represent a more reliable model thanks to the capacity of reproducing the tumor architecture. Here we applied two GET protocols, using a plate or linear electrode, on 3D-cultured HCC1954 and MDA-MB231 breast cancer cell lines grown on a novel collagen-free 3D scaffold and compared results with conventional 2D cultures. To evaluate the electrotransfer efficiency, we used the plasmid pEGFP-C3 encoding the enhanced green fluorescent protein (EGFP) reporter gene. The novel 3D scaffold promoted extracellular matrix deposition, which particularly influences cell behavior in both in vitro cell cultures and in vivo tumor tissue. While the transfection efficiency was similar in the 2D-cultures, we observed significant differences in the 3D-model. The transfection efficiency in the 3D vs 2D model was 44% versus 15% (p < 0.01) and 24% versus 17% (p < 0.01) in HCC1954 and MDA-MB231 cell cultures, respectively. These findings suggest that the novel 3D scaffold allows reproducing, at least partially, the peculiar morphology of the original tumor tissues, thus allowing us to detect meaningful differences between the two cell lines. Following GET with plate electrodes, cell viability was higher in 3D-cultured HCC1954 (66%) and MDA-MB231 (96%) cell lines compared to their 2D counterpart (53% and 63%, respectively, p < 0.001). Based on these results, we propose the novel 3D scaffold as a reliable support for the preparation of cell cultures in GET studies. It may increase the reliability of in vitro assays and allow the optimization of GET parameters of in vivo protocols.

scholarly journals LdrB Toxin with In Vitro and In Vivo Antitumor Activity as a Potential Tool for Cancer Gene Therapy

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 1016 ◽  
Author(s):  
Yaiza Jiménez-Martínez ◽  
Carmen Griñán-Lisón ◽  
Hoda Khaldy ◽  
Ana Martín ◽  
Alba Cambrils ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Therapy ◽  
Side Effects ◽  
Lethal Effect ◽  
Cancer Gene Therapy ◽  
Experimental Models ◽  
Cancer Gene ◽  
Inhibition Of Proliferation

Due to the high prevalence of cancer in recent years, it is necessary to develop new and more effective therapies that produce fewer side effects. Development of gene therapy for cancer based on the use of suicide genes that can damage the tumor cell, without requiring a prodrug for its lethal effect, is one of the recent foci of gene therapy strategies. We evaluated the cytotoxic impact of the LdrB toxin from Escherichia coli k12 as a possible tool for cancer gene therapy. For that, colorectal and breast cancer cells were transfected under the control of a TRE3G promoter inducible by doxycycline. Our results showed that ldrB gene expression induced a drastic inhibition of proliferation in vitro, in both 2D and 3D experimental models. Moreover, unlike conventional chemotherapy, the ldrB gene induced a severe loss of proliferation in vivo without any side effects in our animal model. This antitumor outcome was modulated by cell cycle arrest in the G0/G1 phase and apoptotic death. Scanning electronic microscopy demonstrates that the LdrB toxin conserves its pore-forming ability in HCT-116 cells as in E. coli k12. Taken together, our results provide, for the first time, a proof of concept of the antitumor capacity of the ldrB gene in colorectal and breast cancer.

scholarly journals Targeting transcription of MCL-1 sensitizes HER2-amplified breast cancers to HER2 inhibitors

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Konstantinos V. Floros ◽  
Sheeba Jacob ◽  
Richard Kurupi ◽  
Carter K. Fairchild ◽  
Bin Hu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Growth Factor Receptor ◽  
Myeloid Cell ◽  
Cdk Inhibitors ◽  
The Novel ◽  
Breast Cancers ◽  
Cancer Models ◽  
Epidermal Growth

AbstractHuman epidermal growth factor receptor 2 gene (HER2) is focally amplified in approximately 20% of breast cancers. HER2 inhibitors alone are not effective, and sensitizing agents will be necessary to move away from a reliance on heavily toxic chemotherapeutics. We recently demonstrated that the efficacy of HER2 inhibitors is mitigated by uniformly low levels of the myeloid cell leukemia 1 (MCL-1) endogenous inhibitor, NOXA. Emerging clinical data have demonstrated that clinically advanced cyclin-dependent kinase (CDK) inhibitors are effective MCL-1 inhibitors in patients, and, importantly, well tolerated. We, therefore, tested whether the CDK inhibitor, dinaciclib, could block MCL-1 in preclinical HER2-amplified breast cancer models and therefore sensitize these cancers to dual HER2/EGFR inhibitors neratinib and lapatinib, as well as to the novel selective HER2 inhibitor tucatinib. Indeed, we found dinaciclib suppresses MCL-1 RNA and is highly effective at sensitizing HER2 inhibitors both in vitro and in vivo. This combination was tolerable in vivo. Mechanistically, liberating the effector BCL-2 protein, BAK, from MCL-1 results in robust apoptosis. Thus, clinically advanced CDK inhibitors may effectively combine with HER2 inhibitors and present a chemotherapy-free therapeutic strategy in HER2-amplified breast cancer, which can be tested immediately in the clinic.

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