165 results on '"José Courty"'
Search Results
2. Nucleolin Therapeutic Targeting Decreases Pancreatic Cancer Immunosuppression
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Matteo Ponzo, Anais Debesset, Mélissande Cossutta, Mounira Chalabi-Dchar, Claire Houppe, Caroline Pilon, Alba Nicolas-Boluda, Sylvain Meunier, Fabio Raineri, Allan Thiolat, Rémy Nicolle, Federica Maione, Serena Brundu, Carina Florina Cojocaru, Philippe Bouvet, Corinne Bousquet, Florence Gazeau, Christophe Tournigand, José Courty, Enrico Giraudo, José L. Cohen, and Ilaria Cascone
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vessels ,nucleolin ,immune cells ,PDAC ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background: The pancreatic ductal adenocarcinoma (PDAC) microenvironment is highly fibrotic and hypoxic, with poor immune cell infiltration. Recently, we showed that nucleolin (NCL) inhibition normalizes tumour vessels and impairs PDAC growth. Methods: Immunocompetent mouse models of PDAC were treated by the pseudopeptide N6L, which selectively inhibits NCL. Tumour-infiltrating immune cells and changes in the tumour microenvironment were analysed. Results: N6L reduced the proportion of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) and increased tumour-infiltrated T lymphocytes (TILs) with an activated phenotype. Low-dose anti-VEGFR2 treatment normalized PDAC vessels but did not modulate the immune suppressive microenvironment. RNAseq analysis of N6L-treated PDAC tumours revealed a reduction of cancer-associated fibroblast (CAF) expansion in vivo and in vitro. Notably, N6L treatment decreased IL-6 levels both in tumour tissues and in serum. Treating mPDAC by an antibody blocking IL-6 reduced the proportion of Tregs and MDSCs and increased the amount of TILs, thus mimicking the effects of N6L. Conclusions: These results demonstrate that NCL inhibition blocks the amplification of lymphoid and myeloid immunosuppressive cells and promotes T cell activation in PDAC through a new mechanism of action dependent on the direct inhibition of the tumoral stroma.
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- 2022
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3. Tumor stiffening reversion through collagen crosslinking inhibition improves T cell migration and anti-PD-1 treatment
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Alba Nicolas-Boluda, Javier Vaquero, Lene Vimeux, Thomas Guilbert, Sarah Barrin, Chahrazade Kantari-Mimoun, Matteo Ponzo, Gilles Renault, Piotr Deptula, Katarzyna Pogoda, Robert Bucki, Ilaria Cascone, José Courty, Laura Fouassier, Florence Gazeau, and Emmanuel Donnadieu
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tumor ,extracellular matrix ,T lymphocytes ,immunotherapy ,cell migration ,stiffness ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Only a fraction of cancer patients benefits from immune checkpoint inhibitors. This may be partly due to the dense extracellular matrix (ECM) that forms a barrier for T cells. Comparing five preclinical mouse tumor models with heterogeneous tumor microenvironments, we aimed to relate the rate of tumor stiffening with the remodeling of ECM architecture and to determine how these features affect intratumoral T cell migration. An ECM-targeted strategy, based on the inhibition of lysyl oxidase, was used. In vivo stiffness measurements were found to be strongly correlated with tumor growth and ECM crosslinking but negatively correlated with T cell migration. Interfering with collagen stabilization reduces ECM content and tumor stiffness leading to improved T cell migration and increased efficacy of anti-PD-1 blockade. This study highlights the rationale of mechanical characterizations in solid tumors to understand resistance to immunotherapy and of combining treatment strategies targeting the ECM with anti-PD-1 therapy.
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- 2021
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4. Nucleolin Aptamer N6L Reprograms the Translational Machinery and Acts Synergistically with mTORi to Inhibit Pancreatic Cancer Proliferation
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Mounira Chalabi-Dchar, Elisabeth Cruz, Hichem C. Mertani, Jean-Jacques Diaz, José Courty, Ilaria Cascone, and Philippe Bouvet
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nucleolin ,pancreatic cancer ,translation ,mTOR inhibitor ,combotherapy ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
We previously showed that N6L, a pseudopeptide that targets nucleolin, impairs pancreatic ductal adenocarcinoma (PDAC) growth and normalizes tumor vessels in animal models. In this study, we analyzed the translatome of PDAC cells treated with N6L to identify the pathways that were either repressed or activated. We observed a strong decrease in global protein synthesis. However, about 6% of the mRNAs were enriched in the polysomes. We identified a 5′TOP motif in many of these mRNAs and demonstrated that a chimeric RNA bearing a 5‘TOP motif was up-regulated by N6L. We demonstrated that N6L activates the mTOR pathway, which is required for the translation of these mRNAs. An inhibitory synergistic effect in PDAC cell lines, including patient-derived xenografts and tumor-derived organoids, was observed when N6L was combined with mTOR inhibitors. In conclusion, N6L reduces pancreatic cells proliferation, which then undergoes translational reprogramming through activation of the mTOR pathway. N6L and mTOR inhibitors act synergistically to inhibit the proliferation of PDAC and human PDX cell lines. This combotherapy of N6L and mTOR inhibitors could constitute a promising alternative to treat pancreatic cancer.
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- 2021
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5. The Extracellular Matrix in Pancreatic Cancer: Description of a Complex Network and Promising Therapeutic Options
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Benedetta Ferrara, Cataldo Pignatelli, Mélissande Cossutta, Antonio Citro, José Courty, and Lorenzo Piemonti
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extracellular matrix ,stroma ,stiffness ,solid stress ,matrix remodeling ,cancer-associated fibroblasts ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
The stroma is a relevant player in driving and supporting the progression of pancreatic ductal adenocarcinoma (PDAC), and a large body of evidence highlights its role in hindering the efficacy of current therapies. In fact, the dense extracellular matrix (ECM) characterizing this tumor acts as a natural physical barrier, impairing drug penetration. Consequently, all of the approaches combining stroma-targeting and anticancer therapy constitute an appealing option for improving drug penetration. Several strategies have been adopted in order to target the PDAC stroma, such as the depletion of ECM components and the targeting of cancer-associated fibroblasts (CAFs), which are responsible for the increased matrix deposition in cancer. Additionally, the leaky and collapsing blood vessels characterizing the tumor might be normalized, thus restoring blood perfusion and allowing drug penetration. Even though many stroma-targeting strategies have reported disappointing results in clinical trials, the ECM offers a wide range of potential therapeutic targets that are now being investigated. The dense ECM might be bypassed by implementing nanoparticle-based systems or by using mesenchymal stem cells as drug carriers. The present review aims to provide an overview of the principal mechanisms involved in the ECM remodeling and of new promising therapeutic strategies for PDAC.
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- 2021
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6. Nucleolin Targeting by N6L Inhibits Wnt/β-Catenin Pathway Activation in Pancreatic Ductal Adenocarcinoma
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Fabio Raineri, Sandrine Bourgoin-Voillard, Mélissande Cossutta, Damien Habert, Matteo Ponzo, Claire Houppe, Benoît Vallée, Michele Boniotto, Mounira Chalabi-Dchar, Philippe Bouvet, Anne Couvelard, Jerome Cros, Anais Debesset, José L. Cohen, José Courty, and Ilaria Cascone
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pancreatic ductal adenocarcinoma ,nucleolin ,N6L ,Wnt/β-catenin pathway ,tumor microenvironment ,cancer therapy ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and resistant cancer with no available effective therapy. We have previously demonstrated that nucleolin targeting by N6L impairs tumor growth and normalizes tumor vessels in PDAC mouse models. Here, we investigated new pathways that are regulated by nucleolin in PDAC. We found that N6L and nucleolin interact with β-catenin. We found that the Wnt/β-catenin pathway is activated in PDAC and is necessary for tumor-derived 3D growth. N6L and nucleolin loss of function induced by siRNA inhibited Wnt pathway activation by preventing β-catenin stabilization in PDAC cells. N6L also inhibited the growth and the activation of the Wnt/β-catenin pathway in vivo in mice and in 3D cultures derived from MIA PaCa2 tumors. On the other hand, nucleolin overexpression increased β-catenin stabilization. In conclusion, in this study, we identified β-catenin as a new nucleolin interactor and suggest that the Wnt/β-catenin pathway could be a new target of the nucleolin antagonist N6L in PDAC.
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- 2021
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7. Iron Oxide Nanoparticles as Carriers for DOX and Magnetic Hyperthermia after Intratumoral Application into Breast Cancer in Mice: Impact and Future Perspectives
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Susann Piehler, Heidi Dähring, Julia Grandke, Julia Göring, Pierre Couleaud, Antonio Aires, Aitziber L. Cortajarena, José Courty, Alfonso Latorre, Álvaro Somoza, Ulf Teichgräber, and Ingrid Hilger
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magnetic hyperthermia ,magnetic nanoparticles ,doxorubicin ,breast cancer ,mouse model ,Chemistry ,QD1-999 - Abstract
There is still a need for improving the treatment of breast cancer with doxorubicin (DOX). In this paper, we functionalized magnetic nanoparticles (MNPs) with DOX and studied the DOX-induced antitumor effects in breast cancer cells (BT474) in the presence of magnetic hyperthermia (43 °C, 1 h). We show that i) intratumoral application of DOX-functionalized MNPs (at least at a concentration of 9.6 nmol DOX/100 mm3 tumor volume) combined with magnetic hyperthermia favors tumor regression in vivo, and there is evidence for an increased effect compared to magnetic hyperthermia alone or to the intratumoral application of free DOX and ii) the presence of the pseudopeptide NucAnt (N6L) on the MNP surface might well be beneficial in its function as carrier for MNP internalization into breast cancer cells in vitro, which could further augment the possibility of the induction of intracellular heating spots and cell death in the future.
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- 2020
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8. Pleiotrophin Exerts Its Migration and Invasion Effect through the Neuropilin-1 Pathway
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Rania Elahouel, Charly Blanc, Gilles Carpentier, Sophie Frechault, Ilaria Cascone, Damien Destouches, Jean Delbé, José Courty, and Yamina Hamma-Kourbali
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Pleiotrophin (PTN) is a pleiotropic growth factor that exhibits angiogenic properties and is involved in tumor growth and metastasis. Although it has been shown that PTN is expressed in tumor cells, few studies have investigated its receptors and their involvement in cell migration and invasion. Neuropilin-1 (NRP-1) is a receptor for multiple growth factors that mediates cell motility and plays an important role in angiogenesis and tumor progression. Here we provide evidence for the first time that NRP-1 is crucial for biological activities of PTN. We found that PTN interacted directly with NRP-1 through its thrombospondin type-I repeat domains. Importantly, binding of PTN to NRP-1 stimulated the internalization and recycling of NRP-1 at the cell surface. Invalidation of NRP-1 by RNA interference in human carcinoma cells inhibited PTN-induced intracellular signaling of the serine-threonine kinase, mitogen-activated protein MAP kinase, and focal adhesion kinase pathways. Accordingly, NRP-1 silencing or blocking by antibody inhibited PTN-induced human umbilical vein endothelial cell migration and tumor cell invasion. These results suggest that NRP-1/PTN interaction provides a novel mechanism for controlling the response of endothelial and tumoral cells to PTN and may explain, at least in part, how PTN contributes to tumor angiogenesis and cancer progression.
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- 2015
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9. Pleiotrophin commits human bone marrow mesenchymal stromal cells towards hypertrophy during chondrogenesis.
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Thibault Bouderlique, Emilie Henault, Angelique Lebouvier, Guilhem Frescaline, Phillipe Bierling, Helene Rouard, José Courty, Patricia Albanese, and Nathalie Chevallier
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Medicine ,Science - Abstract
Pleiotrophin (PTN) is a growth factor present in the extracellular matrix of the growth plate during bone development and in the callus during bone healing. Bone healing is a complicated process that recapitulates endochondral bone development and involves many cell types. Among those cells, mesenchymal stromal cells (MSC) are able to differentiate toward chondrogenic and osteoblastic lineages. We aimed to determine PTN effects on differentiation properties of human bone marrow stromal cells (hBMSC) under chondrogenic induction using histological analysis and quantitative reverse transcription polymerase chain reaction. PTN dramatically potentiated chondrogenic differentiation as indicated by a strong increase of collagen 2 protein, and cartilage-related gene expression. Moreover, PTN increased transcription of hypertrophic chondrocyte markers such as MMP13, collagen 10 and alkaline phosphatase and enhanced calcification and the content of collagen 10 protein. These effects are dependent on PTN receptors signaling and PI3 K pathway activation. These data suggest a new role of PTN in bone regeneration as an inducer of hypertrophy during chondrogenic differentiation of hBMSC.
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- 2014
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10. Antitumor and angiostatic activities of the antimicrobial peptide dermaseptin B2.
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Hanneke van Zoggel, Gilles Carpentier, Célia Dos Santos, Yamina Hamma-Kourbali, José Courty, Mohamed Amiche, and Jean Delbé
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Medicine ,Science - Abstract
Recently, we have found that the skin secretions of the Amazonian tree frog Phyllomedusa bicolor contains molecules with antitumor and angiostatic activities and identified one of them as the antimicrobial peptide dermaseptin (Drs) B2. In the present study we further explored the in vitro and in vivo antitumor activity of this molecule and investigated its mechanism of action. We showed that Drs B2 inhibits the proliferation and colony formation of various human tumor cell types, and the proliferation and capillary formation of endothelial cells in vitro. Furthermore, Drs B2 inhibited tumor growth of the human prostate adenocarcinoma cell line PC3 in a xenograft model in vivo. Research on the mechanism of action of Drs B2 on tumor PC3 cells demonstrated a rapid increasing amount of cytosolic lactate dehydrogenase, no activation of caspase-3, and no changes in mitochondrial membrane potential. Confocal microscopy analysis revealed that Drs B2 can interact with the tumor cell surface, aggregate and penetrate the cells. These data together indicate that Drs B2 does not act by apoptosis but possibly by necrosis. In conclusion, Drs B2 could be considered as an interesting and promising pharmacological and therapeutic leader molecule for the treatment of cancer.
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- 2012
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11. Suppression of tumor growth and angiogenesis by a specific antagonist of the cell-surface expressed nucleolin.
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Damien Destouches, Diala El Khoury, Yamina Hamma-Kourbali, Bernard Krust, Patricia Albanese, Panagiotis Katsoris, Gilles Guichard, Jean Paul Briand, José Courty, and Ara G Hovanessian
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Medicine ,Science - Abstract
BACKGROUND: Emerging evidences suggest that nucleolin expressed on the cell surface is implicated in growth of tumor cells and angiogenesis. Nucleolin is one of the major proteins of the nucleolus, but it is also expressed on the cell surface where is serves as a binding protein for variety of ligands implicated in cell proliferation, differentiation, adhesion, mitogenesis and angiogenesis. METHODOLOGY/PRINCIPAL FINDINGS: By using a specific antagonist that binds the C-terminal tail of nucleolin, the HB-19 pseudopeptide, here we show that the growth of tumor cells and angiogenesis are suppressed in various in vitro and in vivo experimental models. HB-19 inhibited colony formation in soft agar of tumor cell lines, impaired migration of endothelial cells and formation of capillary-like structures in collagen gel, and reduced blood vessel branching in the chick embryo chorioallantoic membrane. In athymic nude mice, HB-19 treatment markedly suppressed the progression of established human breast tumor cell xenografts in nude mice, and in some cases eliminated measurable tumors while displaying no toxicity to normal tissue. This potent antitumoral effect is attributed to the direct inhibitory action of HB-19 on both tumor and endothelial cells by blocking and down regulating surface nucleolin, but without any apparent effect on nucleolar nucleolin. CONCLUSION/SIGNIFICANCE: Our results illustrate the dual inhibitory action of HB-19 on the tumor development and the neovascularization process, thus validating the cell-surface expressed nucleolin as a strategic target for an effective cancer drug. Consequently, the HB-19 pseudopeptide provides a unique candidate to consider for innovative cancer therapy.
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- 2008
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12. Supplementary Figure 2 from Nucleolin Targeting Impairs the Progression of Pancreatic Cancer and Promotes the Normalization of Tumor Vasculature
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Ilaria Cascone, Enrico Giraudo, José Courty, Anne Couvelard, Philippe Bouvet, Alberto Bardelli, Simona Lamba, Fabien Mongelard, Christopher Prochasson, Ksenya Shchors, Damien Destouches, Claire Houppe, Silvia Di Maria, Laure Caruana, Gilles Carpentier, Mélissande Cossutta, Federica Maione, and Maud-Emmanuelle Gilles
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NCL blocking antibody and Ncl deletion affects PDAC cell proliferation.
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- 2023
13. Supplementary Table 1 from Nucleolin Targeting Impairs the Progression of Pancreatic Cancer and Promotes the Normalization of Tumor Vasculature
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Ilaria Cascone, Enrico Giraudo, José Courty, Anne Couvelard, Philippe Bouvet, Alberto Bardelli, Simona Lamba, Fabien Mongelard, Christopher Prochasson, Ksenya Shchors, Damien Destouches, Claire Houppe, Silvia Di Maria, Laure Caruana, Gilles Carpentier, Mélissande Cossutta, Federica Maione, and Maud-Emmanuelle Gilles
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Proteome array analysis of angiogenic molecules secreted by ECs.
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- 2023
14. Supplementary Figure 3 from Nucleolin Targeting Impairs the Progression of Pancreatic Cancer and Promotes the Normalization of Tumor Vasculature
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Ilaria Cascone, Enrico Giraudo, José Courty, Anne Couvelard, Philippe Bouvet, Alberto Bardelli, Simona Lamba, Fabien Mongelard, Christopher Prochasson, Ksenya Shchors, Damien Destouches, Claire Houppe, Silvia Di Maria, Laure Caruana, Gilles Carpentier, Mélissande Cossutta, Federica Maione, and Maud-Emmanuelle Gilles
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mPDAC orthopic model characterization.
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- 2023
15. Supplementary Figure 1 from Nucleolin Targeting Impairs the Progression of Pancreatic Cancer and Promotes the Normalization of Tumor Vasculature
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Ilaria Cascone, Enrico Giraudo, José Courty, Anne Couvelard, Philippe Bouvet, Alberto Bardelli, Simona Lamba, Fabien Mongelard, Christopher Prochasson, Ksenya Shchors, Damien Destouches, Claire Houppe, Silvia Di Maria, Laure Caruana, Gilles Carpentier, Mélissande Cossutta, Federica Maione, and Maud-Emmanuelle Gilles
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N6L inhibits PDAC proliferation and migration
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- 2023
16. Data from Nucleolin Targeting Impairs the Progression of Pancreatic Cancer and Promotes the Normalization of Tumor Vasculature
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Ilaria Cascone, Enrico Giraudo, José Courty, Anne Couvelard, Philippe Bouvet, Alberto Bardelli, Simona Lamba, Fabien Mongelard, Christopher Prochasson, Ksenya Shchors, Damien Destouches, Claire Houppe, Silvia Di Maria, Laure Caruana, Gilles Carpentier, Mélissande Cossutta, Federica Maione, and Maud-Emmanuelle Gilles
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Pancreatic cancer is a highly aggressive tumor, mostly resistant to the standard treatments. Nucleolin is overexpressed in cancers and its inhibition impairs tumor growth. Herein, we showed that nucleolin was overexpressed in human specimens of pancreatic ductal adenocarcinoma (PDAC) and that the overall survival significantly increased in patients with low levels of nucleolin. The nucleolin antagonist N6L strongly impaired the growth of primary tumors and liver metastasis in an orthotopic mouse model of PDAC (mPDAC). Similar antitumor effect of N6L has been observed in a highly angiogenic mouse model of pancreatic neuroendocrine tumor RIP-Tag2. N6L significantly inhibited both human and mouse pancreatic cell proliferation and invasion. Notably, the analysis of tumor vasculature revealed a strong increase of pericyte coverage and vessel perfusion both in mPDAC and RIP-Tag2 tumors, in parallel to an inhibition of tumor hypoxia. Nucleolin inhibition directly affected endothelial cell (EC) activation and changed a proangiogenic signature. Among the vascular activators, nucleolin inhibition significantly decreased angiopoietin-2 (Ang-2) secretion and expression in ECs, in the tumor and in the plasma of mPDAC mice. As a consequence of the observed N6L-induced tumor vessel normalization, pre-treatment with N6L efficiently improved chemotherapeutic drug delivery and increased the antitumor properties of gemcitabine in PDAC mice. In conclusion, nucleolin inhibition is a new anti-pancreatic cancer therapeutic strategy that dually blocks tumor progression and normalizes tumor vasculature, improving the delivery and efficacy of chemotherapeutic drugs. Moreover, we unveiled Ang-2 as a potential target and suitable response biomarker for N6L treatment in pancreatic cancer. Cancer Res; 76(24); 7181–93. ©2016 AACR.
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- 2023
17. Supplementary Figure 5 from Nucleolin Targeting Impairs the Progression of Pancreatic Cancer and Promotes the Normalization of Tumor Vasculature
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Ilaria Cascone, Enrico Giraudo, José Courty, Anne Couvelard, Philippe Bouvet, Alberto Bardelli, Simona Lamba, Fabien Mongelard, Christopher Prochasson, Ksenya Shchors, Damien Destouches, Claire Houppe, Silvia Di Maria, Laure Caruana, Gilles Carpentier, Mélissande Cossutta, Federica Maione, and Maud-Emmanuelle Gilles
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N6L and angiogenic molecules regulation.
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- 2023
18. Supplementary Materials and Methods and Supplementary Figure Legends from Nucleolin Targeting Impairs the Progression of Pancreatic Cancer and Promotes the Normalization of Tumor Vasculature
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Ilaria Cascone, Enrico Giraudo, José Courty, Anne Couvelard, Philippe Bouvet, Alberto Bardelli, Simona Lamba, Fabien Mongelard, Christopher Prochasson, Ksenya Shchors, Damien Destouches, Claire Houppe, Silvia Di Maria, Laure Caruana, Gilles Carpentier, Mélissande Cossutta, Federica Maione, and Maud-Emmanuelle Gilles
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The Supplementary data contains the methods and the Supplementary figure legends
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- 2023
19. Supplementary Figure 4 from Nucleolin Targeting Impairs the Progression of Pancreatic Cancer and Promotes the Normalization of Tumor Vasculature
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Ilaria Cascone, Enrico Giraudo, José Courty, Anne Couvelard, Philippe Bouvet, Alberto Bardelli, Simona Lamba, Fabien Mongelard, Christopher Prochasson, Ksenya Shchors, Damien Destouches, Claire Houppe, Silvia Di Maria, Laure Caruana, Gilles Carpentier, Mélissande Cossutta, Federica Maione, and Maud-Emmanuelle Gilles
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Stroma NCL inhibition increases pericyte coverage of tumor blood vessels.
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- 2023
20. Supplementary Figures 1-5, Tables 1-2, and Methods and Materials from A Simple Approach to Cancer Therapy Afforded by Multivalent Pseudopeptides That Target Cell-Surface Nucleoproteins
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José Courty, Jean Paul Briand, Dominique Bagnard, Sylviane Muller, Alain Van Dorsselaer, Jean-Marc Strub, Gilles Carpentier, Marie Maurer, Patricia Albanese, Julien Beyrath, Panagiotis Katsoris, Charalampos Birmpas, Sophie Frechault, Olivier Chaloin, Valérie Machi, Yamina Hamma-Kourbali, Nicolas Page, and Damien Destouches
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Supplementary Figures 1-5, Tables 1-2, and Methods and Materials from A Simple Approach to Cancer Therapy Afforded by Multivalent Pseudopeptides That Target Cell-Surface Nucleoproteins
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- 2023
21. Data from A Simple Approach to Cancer Therapy Afforded by Multivalent Pseudopeptides That Target Cell-Surface Nucleoproteins
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José Courty, Jean Paul Briand, Dominique Bagnard, Sylviane Muller, Alain Van Dorsselaer, Jean-Marc Strub, Gilles Carpentier, Marie Maurer, Patricia Albanese, Julien Beyrath, Panagiotis Katsoris, Charalampos Birmpas, Sophie Frechault, Olivier Chaloin, Valérie Machi, Yamina Hamma-Kourbali, Nicolas Page, and Damien Destouches
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Recent studies have implicated the involvement of cell surface forms of nucleolin in tumor growth. In this study, we investigated whether a synthetic ligand of cell-surface nucleolin known as N6L could exert antitumor activity. We found that N6L inhibits the anchorage-dependent and independent growth of tumor cell lines and that it also hampers angiogenesis. Additionally, we found that N6L is a proapoptotic molecule that increases Annexin V staining and caspase-3/7 activity in vitro and DNA fragmentation in vivo. Through affinity isolation experiments and mass-spectrometry analysis, we also identified nucleophosmin as a new N6L target. Notably, in mouse xenograft models, N6L administration inhibited human tumor growth. Biodistribution studies carried out in tumor-bearing mice indicated that following administration N6L rapidly localizes to tumor tissue, consistent with its observed antitumor effects. Our findings define N6L as a novel anticancer drug candidate warranting further investigation. Cancer Res; 71(9); 3296–305. ©2011 AACR.
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- 2023
22. Supplementary Movie from A Simple Approach to Cancer Therapy Afforded by Multivalent Pseudopeptides That Target Cell-Surface Nucleoproteins
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José Courty, Jean Paul Briand, Dominique Bagnard, Sylviane Muller, Alain Van Dorsselaer, Jean-Marc Strub, Gilles Carpentier, Marie Maurer, Patricia Albanese, Julien Beyrath, Panagiotis Katsoris, Charalampos Birmpas, Sophie Frechault, Olivier Chaloin, Valérie Machi, Yamina Hamma-Kourbali, Nicolas Page, and Damien Destouches
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Supplementary Movie from A Simple Approach to Cancer Therapy Afforded by Multivalent Pseudopeptides That Target Cell-Surface Nucleoproteins
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- 2023
23. 3-O-sulfated heparan sulfate interactors target synaptic adhesion molecules from neonatal mouse brain and inhibit neural activity and synaptogenesis in vitro
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Nazha Sidahmed-Adrar, Olivier Stettler, Damien Habert, T.H. van Kuppevelt, Patrick P. Michel, Walid Redouane, Magda Hamza, José Courty, Mohand Ouidir Ouidja, Auriane Maïza, Carine Dalle, Sandrine Chantepie, Gilles Carpentier, Dulce Papy-Garcia, Croissance cellulaire, réparation et régénération tissulaires (CRRET), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Radboud University Medical Center [Nijmegen], Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Gestionnaire, Hal Sorbonne Université
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Nervous system ,Neurogenesis ,[SDV]Life Sciences [q-bio] ,Synaptogenesis ,lcsh:Medicine ,Peptide ,Hippocampus ,Interactome ,Article ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,medicine ,Animals ,Receptor ,lcsh:Science ,Cells, Cultured ,030304 developmental biology ,Neurons ,chemistry.chemical_classification ,0303 health sciences ,Multidisciplinary ,integumentary system ,Cell adhesion molecule ,lcsh:R ,Glutamate receptor ,Development of the nervous system ,Heparan sulfate ,Synaptic development ,3. Good health ,Cell biology ,[SDV] Life Sciences [q-bio] ,medicine.anatomical_structure ,Reconstructive and regenerative medicine Radboud Institute for Molecular Life Sciences [Radboudumc 10] ,chemistry ,Synapses ,lcsh:Q ,Heparitin Sulfate ,Sulfotransferases ,Heparan Sulfate Proteoglycans ,030217 neurology & neurosurgery ,Neuroscience - Abstract
Heparan sulfate (HS) chains, covalently linked to heparan sulfate proteoglycans (HSPG), promote synaptic development and functions by connecting various synaptic adhesion proteins (AP). HS binding to AP could vary according to modifications of HS chains by different sulfotransferases. 3-O-sulfotransferases (Hs3sts) produce rare 3-O-sulfated HSs (3S-HSs), of poorly known functions in the nervous system. Here, we showed that a peptide known to block herpes simplex virus by interfering with 3S-HSs in vitro and in vivo (i.e. G2 peptide), specifically inhibited neural activity, reduced evoked glutamate release, and impaired synaptic assembly in hippocampal cell cultures. A role for 3S-HSs in promoting synaptic assembly and neural activity is consistent with the synaptic interactome of G2 peptide, and with the detection of Hs3sts and their products in synapses of cultured neurons and in synaptosomes prepared from developing brains. Our study suggests that 3S-HSs acting as receptors for herpesviruses might be important regulators of neuronal and synaptic development in vertebrates.
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- 2020
24. Polymerization-Induced Self-Assembly (PISA) for in situ drug encapsulation or drug conjugation in cancer application
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Hien Phan, Mélissande Cossutta, Claire Houppe, Clémence Le Cœur, Sylvain Prevost, Ilaria Cascone, José Courty, Jacques Penelle, Benoit Couturaud, Institut de Chimie et des Matériaux Paris-Est (ICMPE), and Institut de Chimie du CNRS (INC)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS)
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Drug Carriers ,[CHIM.ORGA]Chemical Sciences/Organic chemistry ,Polymers ,technology, industry, and agriculture ,[CHIM.MATE]Chemical Sciences/Material chemistry ,Surfaces, Coatings and Films ,Electronic, Optical and Magnetic Materials ,Polymerization ,Biomaterials ,[CHIM.POLY]Chemical Sciences/Polymers ,Colloid and Surface Chemistry ,Doxorubicin ,Neoplasms ,Humans ,Methacrylates ,Nanoparticles ,Micelles - Abstract
International audience; Hypothesis: We describe the possibility of using the same block copolymer carriers prepared by PISA for in situ drug encapsulation or drug conjugation.Experiments: Block copolymers containing poly((ethylene glycol) methacrylate)–co-poly (pentafluorophenyl methacrylate)-b-poly(hydroxypropyl methacrylate) (P((PEGMA-co-PFBMA)-b- PHPMA)) were synthesized at 10 wt% using PISA. The first approach involved in situ Doxorubicin (DOX) loading during PISA, while the second exhibited surface functionalization of PISA-made vesicles with dual drug therapies, N-acetyl cysteine (NAC) and DOX using para-fluoro-thiol reaction (PFTR) and carbodiimide chemistry, respectively. Cytotoxicity, cell uptake, and cell apoptosis were assessed on MDA-MB-231 cell lines.Findings: P((PEGMA-co-PFBMA)-b-PHPMA) nanocarriers were prepared, showing size and shape trans- formations from spheres, cylinders to raspberry-forming vesicles. DOX was readily loaded into NPs dur- ing PISA with relatively high encapsulation efficiency of 70 %, whereas the plain PISA-made vesicles could be functionalized with NAC and DOX at high yields. DOX-free NPs showed biocompatibility, whilst DOX- conjugated NPs imparted a concentration-dependent cytotoxicity, as well as an enhanced cell uptake compared to free DOX. The results demonstrated that the same PISA-derived self-assemblies enabled either in situ drug encapsulation, or post-polymerization surface engineering with useful functionalities upon tuning the macro-CTA block, thus holding promises for future drug delivery and biomedical applications.
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- 2021
25. Nucleolin Aptamer N6L Reprograms the Translational Machinery and Acts Synergistically with mTORi to Inhibit Pancreatic Cancer Proliferation
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Philippe Bouvet, José Courty, Elisabeth Cruz, Ilaria Cascone, Mounira Chalabi-Dchar, Jean-Jacques Diaz, Hichem C. Mertani, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Léon Bérard [Lyon], Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), and Courty, José
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Cancer Research ,mTOR inhibitor ,pancreatic cancer ,translation ,[SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB] ,Article ,03 medical and health sciences ,0302 clinical medicine ,nucleolin ,Chimeric RNA ,Pancreatic cancer ,[SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB] ,medicine ,Protein biosynthesis ,PI3K/AKT/mTOR pathway ,RC254-282 ,030304 developmental biology ,0303 health sciences ,Chemistry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Translation (biology) ,medicine.disease ,3. Good health ,Oncology ,Cell culture ,030220 oncology & carcinogenesis ,Cancer research ,combotherapy ,Reprogramming ,Nucleolin - Abstract
Simple Summary Pancreatic cancer is an aggressive disease characterized by its invasiveness, rapid progression, and resistance to conventional therapy. There is a need to identify new molecules to improve current therapies. The aim of this study was to analyze how the pancreatic cancer cells react to the treatment with an inhibitor of nucleolin, N6L. To this end, we analyzed how the translation was affected in the cells during the treatment. We discovered that in response to N6L, a signaling pathway called the mTOR pathway was activated and was involved in the activation of translation of a subset of mRNA that could be involved in the resistance of the cells to the treatment. Indeed, we showed that the combined action of inhibitors of the mTOR pathway with N6L synergistically inhibited the cancer cells’ proliferation. We propose that this new combination of molecules could be a novel therapeutic option for pancreatic cancer. Abstract We previously showed that N6L, a pseudopeptide that targets nucleolin, impairs pancreatic ductal adenocarcinoma (PDAC) growth and normalizes tumor vessels in animal models. In this study, we analyzed the translatome of PDAC cells treated with N6L to identify the pathways that were either repressed or activated. We observed a strong decrease in global protein synthesis. However, about 6% of the mRNAs were enriched in the polysomes. We identified a 5′TOP motif in many of these mRNAs and demonstrated that a chimeric RNA bearing a 5‘TOP motif was up-regulated by N6L. We demonstrated that N6L activates the mTOR pathway, which is required for the translation of these mRNAs. An inhibitory synergistic effect in PDAC cell lines, including patient-derived xenografts and tumor-derived organoids, was observed when N6L was combined with mTOR inhibitors. In conclusion, N6L reduces pancreatic cells proliferation, which then undergoes translational reprogramming through activation of the mTOR pathway. N6L and mTOR inhibitors act synergistically to inhibit the proliferation of PDAC and human PDX cell lines. This combotherapy of N6L and mTOR inhibitors could constitute a promising alternative to treat pancreatic cancer.
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- 2021
26. Author response: Tumor stiffening reversion through collagen crosslinking inhibition improves T cell migration and anti-PD-1 treatment
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Gilles Renault, Katarzyna Pogoda, Florence Gazeau, Alba Nicolas-Boluda, Matteo Ponzo, Robert Bucki, Emmanuel Donnadieu, José Courty, Ilaria Cascone, Chahrazade Kantari-Mimoun, Javier Vaquero, Sarah Barrin, Laura Fouassier, Piotr Deptuła, Lene Vimeux, and Thomas Guilbert
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Chemistry ,Anti pd 1 ,Reversion ,T cell migration ,Cancer research ,Stiffening - Published
- 2021
27. Cell surface nucleolin as active bait for nanomedicine in cancer therapy: a promising option
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Benedetta Ferrara, Benoit Vallée, Sabrina Belbekhouche, José Courty, Ilaria Cascone, Claire Houppe, Damien Habert, Sandrine Bourgoin-Voillard, José L. Cohen, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Institut de Chimie et des Matériaux Paris-Est (ICMPE), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Laboratory of Fundamental and Applied Bioenergetics = Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA), Centre Hospitalier Universitaire [Grenoble] (CHU), PROteomics and METabolomics Platform [Grenoble] (PROMETHEE), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut de Chimie du CNRS (INC)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Translational Innovation in Medicine and Complexity / Recherche Translationnelle et Innovation en Médecine et Complexité - UMR 5525 (TIMC ), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Electrical and Information Engineering Department, Politecnico di Bari, Politecnico di Bari, Laboratoire de recherche sur la croissance cellulaire, la réparation et la régénération tissulaires (LRCCRRT), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Courty, José, and Université Paris-Est (UPE)
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Tumor targeting ,[SDV.BIO]Life Sciences [q-bio]/Biotechnology ,[SDV]Life Sciences [q-bio] ,theranostic ,Cell ,Normal tissue ,Gene Expression ,02 engineering and technology ,Ligands ,01 natural sciences ,Theranostic Nanomedicine ,Neoplasms ,General Materials Science ,Molecular Targeted Therapy ,ComputingMilieux_MISCELLANEOUS ,Drug Carriers ,RNA-Binding Proteins ,Aptamers, Nucleotide ,021001 nanoscience & nanotechnology ,3. Good health ,medicine.anatomical_structure ,Oligodeoxyribonucleotides ,Mechanics of Materials ,Nanomedicine ,0210 nano-technology ,Materials science ,Cancer therapy ,Antineoplastic Agents ,Bioengineering ,Context (language use) ,010402 general chemistry ,nucleolin ,medicine ,[CHIM]Chemical Sciences ,HMGB2 Protein ,Humans ,cancer ,Electrical and Electronic Engineering ,Mechanical Engineering ,Cancer ,General Chemistry ,Phosphoproteins ,medicine.disease ,Peptide Fragments ,[SDV.BIO] Life Sciences [q-bio]/Biotechnology ,0104 chemical sciences ,Cancer research ,nanoparticles ,Peptides ,Nucleolin - Abstract
Conventional chemotherapy used against cancer is mostly limited due to their non-targeted nature, affecting normal tissue and causing undesirable toxic effects to the affected tissue. With the aim of improving these treatments both therapeutically and in terms of their safety, numerous studies are currently being carried out using nanoparticles (NPs) as a vector combining tumor targeting and carrying therapeutic tools. In this context, it appears that nucleolin, a molecule over-expressed on the surface of tumor cells, is an interesting therapeutic target. Several ligands, antagonists of nucleolin of various origins, such as AS1411, the F3 peptide and the multivalent pseudopeptide N6L have been developed and studied as therapeutic tools against cancer. Over the last ten years or so, numerous studies have been published demonstrating that these antagonists can be used as tumor targeting agents with NPs from various origins. Focusing on nucleolin ligands, the aim of this article is to review the literature recently published or under experimentation in our research team to evaluate the efficacy and future development of these tools as anti-tumor agents.
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- 2021
28. N6L-functionalized nanoparticles for targeted and inhibited pancreatic cancer cells
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Damien Habert, Ilaria Cascone, Tina Modjinou, Sena Hamadi, José Courty, Sabrina Belbekhouche, Mélissande Cossutta, Institut de Chimie et des Matériaux Paris-Est (ICMPE), Institut de Chimie du CNRS (INC)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Croissance cellulaire, réparation et régénération tissulaires (CRRET), and Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS)
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Chemistry ,Nanoparticle ,Context (language use) ,02 engineering and technology ,010402 general chemistry ,021001 nanoscience & nanotechnology ,01 natural sciences ,Nanocapsules ,0104 chemical sciences ,3. Good health ,Allylamine ,chemistry.chemical_compound ,Colloid and Surface Chemistry ,Colloidal gold ,Cancer cell ,Drug delivery ,Zeta potential ,Biophysics ,[CHIM]Chemical Sciences ,0210 nano-technology ,ComputingMilieux_MISCELLANEOUS - Abstract
Pancreatic cancer is a growing cause of concern, leading to an increasing number of deaths worldwide. Most of the antitumor drugs for pancreatic cancer are given by systemic administration. However, even if this is at therapeutic doses, its tends to lead to severe side-effects because of nonspecific uptake by healthy tissues. In this context, we aim to develop an innovative drug delivery approach for the treatment of pancreatic cancer based on tailor-made nanomaterials with presenting controlled size, chemistry and stiffness. In this study, we have designed tailor-made N6L-nanomaterials, via the combination of both a templating method and a self-assembly process onto colloidal gold nanoparticles (diameters 20 nm and 60 nm) using a core template. The removal of the core leads to hollow particles, also called capsules. We judiciously functionalised the outer layer of the nanomaterial with N6L, which corresponds to a synthetic agent that is non-toxic to normal mammalian cells, targets surface nucleolin and induces tumour cell death by apoptosis. Our data demonstrated, via quartz crystal microbalance measurement, the possibility of directly using N6L in a self-assembly process through electrostatic interactions. In addition, as shown by measuring zeta potential values, we showed that electrostatic interactions between the protonated amine groups of poly (allylamine) macromolecules (+40 mV), the sulphate groups of dextran derivatives (−20 mV) and the protonated amine groups of N6L (+20 mV) are the driving attraction force during multilayer fabrication onto colloidal gold. Transmission electron microscopy was used to confirm that the gold nanoparticles were coated and the nanocapsules were formed. Finally, we successfully showed that these N6L-based nanostructures target cancer cells and inhibited, in a dose dependent manner, cell survival in pancreatic cancer model. This result clearly highlights the potential antitumor activity of the developed nanostructures.
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- 2020
29. Tumor stiffening reversion through collagen crosslinking inhibition improves T cell migration and anti-PD-1 treatment
- Author
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Robert Bucki, Laura Fouassier, Katarzyna Pogoda, Florence Gazeau, Alba Nicolas-Boluda, Matteo Ponzo, Gilles Renault, Piotr Deptuła, Chahrazade Kantari-Mimoun, Emmanuel Donnadieu, José Courty, Javier Vaquero, Ilaria Cascone, and Sarah Barrin
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Extracellular matrix ,Tumor microenvironment ,Chemistry ,In vivo ,medicine.medical_treatment ,medicine ,T cell migration ,Cancer research ,Reversion ,Cancer ,Lysyl oxidase ,Immunotherapy ,medicine.disease - Abstract
Only a fraction of cancer patients benefits from immune checkpoint inhibitors. This may be partly due to the dense extracellular matrix (ECM) that forms a barrier for T cells. Comparing 5 preclinical mouse tumor models with heterogeneous tumor microenvironments, we aimed to relate the rate of tumor stiffening with the remodeling of ECM architecture and to determine how these features affect intratumoral T cell migration. An ECM-targeted strategy, based on the inhibition of lysyl oxidase (LOX) was used. In vivo stiffness measurements were found to be strongly correlated with tumor growth and ECM crosslinking but negatively correlated with T cell migration. Interfering with collagen stabilization reduces ECM content and tumor stiffness leading to improved T cell migration and increased efficacy of anti-PD-1 blockade. This study highlights the rationale of mechanical characterizations in solid tumors to understand resistance to immunotherapy and of combining treatment strategies targeting the ECM with anti-PD-1 therapy.
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- 2020
30. Aerosol-Assisted Synthesis of Tailor-Made Hollow Mesoporous Silica Microspheres for Controlled Release of Antibacterial and Anticancer Agents
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Jalal Poostforooshan, Masoom Shaban, Sabrina Belbekhouche, Alfred P. Weber, Vanessa Alphonse, Noureddine Bousserrhine, Damien Habert, José Courty, Molecular virology and immunology – Physiopathology and therapeutic of chronic viral hepatitis (Team 18) (Inserm U955), Institut Mondor de Recherche Biomédicale (IMRB), and Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)
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Materials science ,Colloidal silica ,Nanoparticle ,Antineoplastic Agents ,02 engineering and technology ,010402 general chemistry ,01 natural sciences ,Drug Delivery Systems ,[SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication ,Cell Line, Tumor ,Escherichia coli ,Humans ,General Materials Science ,Particle Size ,ComputingMilieux_MISCELLANEOUS ,Cell Proliferation ,Aerosols ,Drug Carriers ,Mesoporous silica ,Silicon Dioxide ,021001 nanoscience & nanotechnology ,Controlled release ,Microspheres ,Anti-Bacterial Agents ,3. Good health ,0104 chemical sciences ,Chemical engineering ,Delayed-Action Preparations ,Drug delivery ,Nanoparticles ,Particle size ,0210 nano-technology ,Mesoporous material ,Drug carrier ,Porosity - Abstract
Hollow mesoporous silica microsphere (HMSM) particles are one of the most promising vehicles for efficient drug delivery owing to their large hollow interior cavity for drug loading and the permeable mesoporous shell for controlled drug release. Here, we report an easily controllable aerosol-based approach to produce HMSM particles by continuous spray-drying of colloidal silica nanoparticles and Eudragit/Triton X100 composite (EUT) nanospheres as templates, followed by template removal. Importantly, the internal structure of the hollow cavity and the external morphology and the porosity of the mesoporous shell can be tuned to a certain extent by adjusting the experimental conditions (i.e., silica to EUT mass ratio and particle size of silica nanoparticles) to optimize the drug loading capacity and the controlled-release properties. Then, the application of aerosol-synthesized HMSM particles in controlled drug delivery was investigated by loading amoxicillin as an antibiotic compound with high entrapment efficiency (up to 46%). Furthermore, to improve the biocompatibility of the amoxicillin-loaded HMSM particles, their surfaces were functionalized with poly(allylamine hydrochloride) and alginate as biocompatible polymers via the layer-by-layer assembly. The resulting particles were evaluated toward Escherichia coli (Gram-negative) bacteria and indicated the bacterial inhibition up to 90% in less than 2 h. Finally, we explored the versatility of HMSMs as drug carriers for pancreatic cancer treatment. Because the pH value of the extracellular medium in pancreatic tumors is lower than that of the healthy tissue, chitosan as a pH-sensitive gatekeeper was grafted to the HMSM surface and then loaded with a pro-apoptotic NCL antagonist agent (N6L) as an anticancer drug. The obtained particles exhibited pH-responsive drug releases and excellent anticancer activities with inhibition of cancer cell growth up to 60%.
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- 2020
31. Iron oxide nanoparticles as carriers for DOX and magnetic hyperthermia after intratumoral application into breast cancer in mice: impact and future perspectives
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Ulf Teichgräber, Aitziber L. Cortajarena, Susann Piehler, Alfonso Latorre, Julia Göring, Antonio Aires, Álvaro Somoza, José Courty, Pierre Couleaud, Ingrid Hilger, Heidi Dähring, Julia Grandke, INSERM Immunomodulation et Biothérapie (IBIOT), European Commission, Ministerio de Ciencia, Innovación y Universidades (España), and Agencia Estatal de Investigación (España)
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Programmed cell death ,magnetic nanoparticles ,General Chemical Engineering ,media_common.quotation_subject ,mouse model ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,doxorubicin ,Article ,Mouse model ,lcsh:Chemistry ,03 medical and health sciences ,chemistry.chemical_compound ,Breast cancer ,0302 clinical medicine ,breast cancer ,In vivo ,medicine ,polycyclic compounds ,Magnetic hyperthermia ,General Materials Science ,Doxorubicin ,magnetic hyperthermia ,Internalization ,skin and connective tissue diseases ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,media_common ,0303 health sciences ,Chemistry ,technology, industry, and agriculture ,medicine.disease ,3. Good health ,carbohydrates (lipids) ,lcsh:QD1-999 ,030220 oncology & carcinogenesis ,Magnetic nanoparticles ,Cancer research ,human activities ,Iron oxide nanoparticles ,medicine.drug - Abstract
© 2020 by the authors., There is still a need for improving the treatment of breast cancer with doxorubicin (DOX). In this paper, we functionalized magnetic nanoparticles (MNPs) with DOX and studied the DOX-induced antitumor effects in breast cancer cells (BT474) in the presence of magnetic hyperthermia (43 °C, 1 h). We show that i) intratumoral application of DOX-functionalized MNPs (at least at a concentration of 9.6 nmol DOX/100 mm3 tumor volume) combined with magnetic hyperthermia favors tumor regression in vivo, and there is evidence for an increased effect compared to magnetic hyperthermia alone or to the intratumoral application of free DOX and ii) the presence of the pseudopeptide NucAnt (N6L) on the MNP surface might well be beneficial in its function as carrier for MNP internalization into breast cancer cells in vitro, which could further augment the possibility of the induction of intracellular heating spots and cell death in the future., The described work was carried out within the project “Multifunctional Nanoparticles for the Selective Detection and Treatment of Cancer” (Multifun), funded by the European Commission (Nr. 262943) and in parts by the European Union’s Horizon 2020 research and innovation program under grant agreement No 685795 and the Spanish Ministry of Economy and Competitiveness (SAF2017-87305-R). IMDEA Nanociencia acknowledges support from the ‘Severo Ochoa’ Programme for Centres of Excellence in R&D (MINECO, Grant SEV-2016-0686).
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- 2020
32. The Nucleolin Antagonist N6L Inhibits LINE1 Retrotransposon Activity in Non-Small Cell Lung Carcinoma Cells
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Marco A. Tavera-Garcia, Elsa M. Reyes-Reyes, Ilaria Cascone, Isabel Runge, Kenneth S. Ramos, José Courty, Sara Moore, University of Arizona, Croissance cellulaire, réparation et régénération tissulaires (CRRET), and Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS)
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Somatic cell ,Retrotransposon ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,[SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC] ,Biology ,NSCLC ,03 medical and health sciences ,0302 clinical medicine ,and Lung cancer ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,medicine ,Lung cancer ,030304 developmental biology ,Nucleolin ,0303 health sciences ,Gene knockdown ,LINE1 ,medicine.disease ,Reverse transcriptase ,3. Good health ,Long interspersed nuclear element ,Oncology ,Cell culture ,030220 oncology & carcinogenesis ,Cancer research ,Research Paper - Abstract
International audience; Lung cancer is the most common cause of cancer death in the United States. The genome of non-small cell lung cancer (NSCLC), the most frequent lung cancer type, is strongly affected by Long Interspersed Nuclear Element (LINE1) insertions. Active LINE1s are repetitive DNA sequences that can amplify themselves in the genome utilizing a retrotransposition mechanism whereby LINE1 is copied via reverse transcription and inserted at target sites. ORF1p and ORF2p are LINE1 encoded proteins essential for LINE1 retrotransposition. LINE1s are silenced epigenetically in somatic tissues, and their reactivation has been associated with cancer pathogenesis. Here, we present evidence that nucleolin (NCL) regulates expression of LINE1-ORF1p (L1-ORF1p) in NSCLC cells. Genetic knockdown of NCL significantly inhibited expression of L1-ORF1p in various NSCLC cell lines. Treatment with the investigational NCL antagonist N6L ablated L1-ORF1p expression in all cell lines constitutively expressing L1-ORFp. N6L displayed a stronger antiproliferative activity in NSCLC tumor cell lines expressing the highest L1-ORF1p protein levels. Moreover, N6L treatment of nude mice bearing NSCLC tumor xenografts blocked L1-ORF1p expression and effectively inhibited tumor growth. These data indicate that L1-ORF1p expression is regulated by NCL and identify NCL as a novel promising target for pharmacological inhibition of LINE1.
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- 2020
33. Nucleolin Targeting by N6L Inhibits Wnt/β-Catenin Pathway Activation in Pancreatic Ductal Adenocarcinoma
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José Cohen, Sandrine Bourgoin-Voillard, Philippe Bouvet, Damien Habert, Mounira Chalabi-Dchar, Claire Houppe, Ilaria Cascone, Mélissande Cossutta, Benoît Vallée, José Courty, Matteo Ponzo, Anais Debesset, Jérôme Cros, Fabio Raineri, Michele Boniotto, Anne Couvelard, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and COSSUTTA, Mélissande
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0301 basic medicine ,Cancer Research ,Pancreatic ductal adenocarcinoma ,endocrine system diseases ,pancreatic ductal adenocarcinoma ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Article ,03 medical and health sciences ,nucleolin ,0302 clinical medicine ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,In vivo ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Wnt/β-catenin pathway ,tumor microenvironment ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,RC254-282 ,Loss function ,N6L ,Tumor microenvironment ,Chemistry ,Wnt signaling pathway ,Antagonist ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,[SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,[SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,digestive system diseases ,3. Good health ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Catenin ,Cancer research ,cancer therapy ,Nucleolin - Abstract
Simple Summary Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that has no effective treatment. Nucleolin targeting by the pseudopeptide N6L inhibits the tumor growth and metastasis of pancreatic ductal adenocarcinoma (PDAC). Here, we explored the pathways regulated by nucleolin and N6L in PDAC. We demonstrated that both interact with β-catenin, and that the Wnt/β-catenin pathway is activated in PDAC mouse models. Nucleolin inhibition decreases Wnt/β-catenin pathway activation in PDAC cells and tumors, and represents a new druggable pathway regulated by nucleolin. Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and resistant cancer with no available effective therapy. We have previously demonstrated that nucleolin targeting by N6L impairs tumor growth and normalizes tumor vessels in PDAC mouse models. Here, we investigated new pathways that are regulated by nucleolin in PDAC. We found that N6L and nucleolin interact with β-catenin. We found that the Wnt/β-catenin pathway is activated in PDAC and is necessary for tumor-derived 3D growth. N6L and nucleolin loss of function induced by siRNA inhibited Wnt pathway activation by preventing β-catenin stabilization in PDAC cells. N6L also inhibited the growth and the activation of the Wnt/β-catenin pathway in vivo in mice and in 3D cultures derived from MIA PaCa2 tumors. On the other hand, nucleolin overexpression increased β-catenin stabilization. In conclusion, in this study, we identified β-catenin as a new nucleolin interactor and suggest that the Wnt/β-catenin pathway could be a new target of the nucleolin antagonist N6L in PDAC.
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- 2021
34. Multivalent cationic pseudopeptide polyplexes as a tool for cancer therapy
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José Courty, Benoit Vallée, Ilaria Cascone, Zoi Diamantopoulou, Eric Leroy, Federica Maione, Maud-Emmanuelle Gilles, Blandine Brissault, Maha Sader, Jacques Penelle, Damien Habert, Mélissande Cossutta, Claire Houppe, Damien Destouches, Enrico Giraudo, Croissance cellulaire, réparation et régénération tissulaires (CRRET), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie et des Matériaux Paris-Est (ICMPE), and Institut de Chimie du CNRS (INC)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS)
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0301 basic medicine ,Biodistribution ,Pancreatic ductal adenocarcinoma ,Cancer therapy ,Antitumour activity ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,[CHIM.THER]Chemical Sciences/Medicinal Chemistry ,02 engineering and technology ,03 medical and health sciences ,In vivo ,Pancreatic cancer ,medicine ,ComputingMilieux_MISCELLANEOUS ,Nucleolin ,business.industry ,Nanoparticles ,Polyplex ,Oncology ,Cancer ,021001 nanoscience & nanotechnology ,medicine.disease ,Gemcitabine ,3. Good health ,030104 developmental biology ,Immunology ,Cancer research ,0210 nano-technology ,business ,Research Paper ,medicine.drug - Abstract
// Zoi Diamantopoulou 1, * , Maud-Emmanuelle Gilles 1, * , Maha Sader 1 , Melissande Cossutta 1 , Benoit Vallee 1 , Claire Houppe 1 , Damien Habert 1 , Blandine Brissault 2 , Eric Leroy 2 , Federica Maione 3 , Enrico Giraudo 3 , Damien Destouches 1 , Jacques Penelle 2 , Jose Courty 1, ** and Ilaria Cascone 1, ** 1 Laboratory of Growth, Reparation and Tissue Regeneration (CRRET), University of Paris Est, ERL-CNRS 9215, 94010 Creteil, France 2 East Paris Institute of Chemistry and Materials Science, CNRS & University Paris-Est, 94320 Thiais, France 3 Department of Oncological Sciences and Laboratory of Transgenic Mouse Models, Institute for Cancer Research and Treatment, University of Torino School of Medicine, I-10060 Candiolo, Torino, Italy * These authors have contributed equally to this work ** These authors are considered as co-senior author Correspondence to: Jose Courty, email: courty@u-pec.fr Keywords: nanoparticles, antitumour activity, polyplex, nucleolin, pancreatic ductal adenocarcinoma Received: June 21, 2017 Accepted: August 27, 2017 Published: September 30, 2017 ABSTRACT In this study, a novel anticancer reagent based on polyplexes nanoparticles was developed. These nanoparticles are obtained by mixing negatively charged polyelectrolytes with the antitumour cationically-charged pseudopeptide N6L. Using two in vivo experimental tumor pancreatic models based upon PANC-1 and mPDAC cells, we found that the antitumour activity of N6L is significantly raised via its incorporation in polyplexed nanoparticles. Study of the mechanism of action using affinity isolation and si-RNA experiments indicated that N6L-polyplexes are internalized through their interaction with nucleolin. In addition, using a very aggressive model of pancreatic cancer in which gemcitabine, a standard of care for this type of cancer, has a weak effect on tumour growth, we observed that N6L-polyplexes administration has a stronger efficacy than gemcitabine. Biodistribution studies carried out in tumour-bearing mice indicated that N6L-polyplexes localises in tumour tissue, in agreement with its antitumour effect. These results support the idea that N6L nanoparticles could develop into a promising strategy for the treatment of cancer, especially hard-to-treat pancreatic cancers.
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- 2017
35. The phenotype of target pancreatic cancer cells influences cell death by magnetic hyperthermia with nanoparticles carrying gemicitabine and the pseudo-peptide NucAnt
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Pierre Couleaud, Yuri Volkov, Adriele Prina-Mello, Alfonso Latorre, José Courty, Mourad Sanhaji, Julia Göring, Álvaro Somoza, Aitziber L. Cortajarena, Rodolfo Miranda, Ingrid Hilger, Marcus Stapf, Robert Ludwig, Antonio Aires, Croissance cellulaire, réparation et régénération tissulaires (CRRET), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Centre for Research on Adaptive Nanostructures and Nanodevices, Trinity College Dublin, Institutfür DiagnostischeundInterventionelle RadiologieI, Friedrich-Schiller-Universität = Friedrich Schiller University Jena [Jena, Germany], Laboratoire CRRET, EAC/CNRS-7149, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Instituto IMDEA Nanociencia [Madrid], and Instituto Imdea Nanociencia
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Cell ,Pharmaceutical Science ,Medicine (miscellaneous) ,Apoptosis ,02 engineering and technology ,Deoxycytidine ,S Phase ,Pancreatic tumor ,Cytotoxic T cell ,General Materials Science ,Magnetite Nanoparticles ,ComputingMilieux_MISCELLANEOUS ,0303 health sciences ,Chemistry ,021001 nanoscience & nanotechnology ,3. Good health ,Tumor Burden ,medicine.anatomical_structure ,Phenotype ,Molecular Medicine ,[SDV.IB]Life Sciences [q-bio]/Bioengineering ,0210 nano-technology ,medicine.drug ,Programmed cell death ,Biomedical Engineering ,NucAnt (N6L) ,Mice, Nude ,Bioengineering ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Mouse model ,03 medical and health sciences ,Pancreatic cancer ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Magnetic hyperthermia ,Gemcitabine (Gem) ,030304 developmental biology ,Cell Proliferation ,Magnetic nanoparticles (MNP) ,JNK Mitogen-Activated Protein Kinases ,Cell Cycle Checkpoints ,Hyperthermia, Induced ,medicine.disease ,Xenograft Model Antitumor Assays ,Gemcitabine ,Pancreatic Neoplasms ,Ki-67 Antigen ,Cell culture ,Cancer research ,Peptides - Abstract
International audience; In this paper we show that conjugation of magnetic nanoparticles (MNPs) with Gemcitabine and/or NucAnt (N6L) fostered their internalization into pancreatic tumor cells and that the coupling procedure did not alter the cytotoxic potential of the drugs. By treating tumor cells (BxPC3 and PANC-1) with the conjugated MNPs and magnetic hyperthermia (43°C, 60 min), cell death was observed. The two pancreatic tumor cell lines showed different reactions against the combined therapy according to their intrinsic sensitivity against Gemcitabine (cell death, ROS production, ability to activate ERK 1/2 and JNK). Finally, tumors (e.g. 3 mL) could be effectively treated by using almost 4.2 × 10 5 times lower Gemcitabine doses compared to conventional therapies. Our data show that this combinatorial therapy might well play an important role in certain cell phenotypes with low readiness of ROS production. This would be of great significance in distinctly optimizing local pancreatic tumor treatments.
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- 2019
36. Antagonist of nucleolin, N6L, inhibits neovascularization in mouse models of retinopathies
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Laure Caruana, Claire Houppe, Lucile Vignaud, Xavier Guilloneau, José Courty, Damien Habert, Maud-Emmanuelle Gilles, Mélissande Cossutta, Marie Darche, Michel Paques, Ilaria Cascone, Molecular virology and immunology – Physiopathology and therapeutic of chronic viral hepatitis (Team 18) (Inserm U955), Institut Mondor de Recherche Biomédicale (IMRB), and Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)
- Subjects
Angiogenesis ,Angiogenesis Inhibitors ,Biochemistry ,Neovascularization ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Retinal Diseases ,[SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB] ,Genetics ,medicine ,Animals ,Phosphorylation ,Molecular Biology ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,Cell Proliferation ,0303 health sciences ,business.industry ,RNA-Binding Proteins ,Retinopathy of prematurity ,Diabetic retinopathy ,medicine.disease ,Phosphoproteins ,eye diseases ,Choroidal Neovascularization ,3. Good health ,Endothelial stem cell ,Mice, Inbred C57BL ,Oxygen ,Disease Models, Animal ,Choroidal neovascularization ,Intravitreal Injections ,030221 ophthalmology & optometry ,Cancer research ,sense organs ,medicine.symptom ,business ,Peptides ,Nucleolin ,Biotechnology ,Retinopathy - Abstract
Retinal vascular diseases (RVD) have been identified as a major cause of blindness worldwide. These pathologies, including the wet form of age-related macular degeneration, retinopathy of prematurity, and diabetic retinopathy are currently treated by intravitreal delivery of anti-vascular endothelial growth factor (VEGF) agents. However, repeated intravitreal injections can lead to ocular complications and resistance to these treatments. Thus, there is a need to find new targeted therapies. Nucleolin regulates the endothelial cell (EC) activation and angiogenesis. In previous studies, we designed a pseudopeptide, N6L, that binds the nucleolin and blocks the tumor angiogenesis. In this study, the effect of N6L was investigated in two experimental models of retinopathies including oxygen-induced retinopathy (OIR) and choroidal neovascularization (CNV). We found that in mouse OIR, intraperitoneal injection of N6L is delivered to activated ECs and induced a 50% reduction of pathological neovascularization. The anti-angiogenic effect of N6L has been tested in CNV model in which the systemic injection of N6L induced a 33% reduction of angiogenesis. This effect is comparable to those obtained with VEGF-trap, a standard of care drug for RVD. Interestingly, with preventive and curative treatments, neoangiogenesis is inhibited by 59%. Our results have potential interest in the development of new therapies targeting other molecules than VEGF for RVD.
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- 2019
37. Weibel-Palade Bodies Orchestrate Pericytes During Angiogenesis
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Gilles Carpentier, Emilie Picard, Fabio Raineri, Ilaria Cascone, José Courty, Cécile V. Denis, Caterina Casari, Mélissande Cossutta, Delphine Villain, Michel Paques, Benoit Vallée, Matteo Ponzo, Maud-Emmanuelle Gilles, Marie Darche, Claire Houppe, Institut Mondor de Recherche Biomédicale (IMRB), Croissance cellulaire, réparation et régénération tissulaires (CRRET), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Institut de la Vision, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Neurobiologie et Psychiatrie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO), Laboratoire CRRET, EAC/CNRS-7149, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)
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0301 basic medicine ,Vascular Endothelial Growth Factor A ,Angiogenesis ,[SDV]Life Sciences [q-bio] ,Neovascularization, Physiologic ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,[SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC] ,Exocytosis ,Retina ,Angiopoietin-2 ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Von Willebrand factor ,Neoplasms ,Organelle ,Weibel–Palade body ,Animals ,Humans ,ComputingMilieux_MISCELLANEOUS ,Cells, Cultured ,biology ,Neovascularization, Pathologic ,Weibel-Palade Bodies ,Chemistry ,Angiopoietin 2 ,Endothelial Cells ,Cell biology ,Vascular endothelial growth factor ,Endothelial stem cell ,Mice, Inbred C57BL ,030104 developmental biology ,030220 oncology & carcinogenesis ,cardiovascular system ,biology.protein ,Cardiology and Cardiovascular Medicine ,Pericytes - Abstract
Objective Weibel-Palade bodies (WPBs) are endothelial cell (EC)-specific organelles formed by vWF (von Willebrand factor) polymerization and that contain the proangiogenic factor Ang-2 (angiopoietin-2). WPB exocytosis has been shown to be implicated for vascular repair and inflammatory responses. Here, we investigate the role of WPBs during angiogenesis and vessel stabilization. Approach and Results WPB density in ECs decreased at the angiogenic front of retinal vascular network during development and neovascularization compared with stable vessels. In vitro, VEGF (vascular endothelial growth factor) induced a VEGFR-2 (vascular endothelial growth factor receptor-2)-dependent exocytosis of WPBs that contain Ang-2 and consequently the secretion of vWF and Ang-2. Blocking VEGF-dependant WPB exocytosis and Ang-2 secretion promoted pericyte migration toward ECs. Pericyte migration was inhibited by adding recombinant Ang-2 or by silencing Ang-1 (angiopoietin-1) or Tie2 (angiopoietin-1 receptor) in pericytes. Consistently, in vivo anti-VEGF treatment induced accumulation of WPBs in retinal vessels because of the inhibition of WPB exocytosis and promoted the increase of pericyte coverage of retinal vessels during angiogenesis. In tumor angiogenesis, depletion of WPBs in vWF knockout tumor-bearing mice promoted an increase of tumor angiogenesis and a decrease of pericyte coverage of tumor vessels. By another approach, normalized tumor vessels had higher WPB density. Conclusions We demonstrate that WPB exocytosis and Ang-2 secretion are regulated during angiogenesis to limit pericyte coverage of remodeling vessels by disrupting Ang-1/Tie2 autocrine signaling in pericytes.
- Published
- 2019
38. Nucleolin Promotes Heat Shock–Associated Translation of VEGF-D to Promote Tumor Lymphangiogenesis
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Stefano Marzi, Stéphanie Cassant-Sourdy, José Courty, Aurelien Adoue, Anne-Catherine Prats, Frédéric Lopez, Anne-Catherine Helfer, Julie Guillermet-Guibert, Barbara Garmy-Susini, Anne Gomez-Brouchet, Robert J. Schneider, Françoise Pujol, Fransky Hantelys, Laetitia Ligat, Stéphane Pyronnet, Florent Morfoisse, Florence Tatin, Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), and Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
0301 basic medicine ,Cancer Research ,[SDV]Life Sciences [q-bio] ,Vascular Endothelial Growth Factor D ,Biology ,Transfection ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Protein biosynthesis ,Animals ,Humans ,Gene silencing ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Lymphangiogenesis ,ComputingMilieux_MISCELLANEOUS ,Messenger RNA ,fungi ,RNA-Binding Proteins ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,Translation (biology) ,Phosphoproteins ,Molecular biology ,3. Good health ,Cell biology ,Vascular endothelial growth factor ,Internal ribosome entry site ,030104 developmental biology ,Oncology ,chemistry ,Nucleolin - Abstract
The vascular endothelial growth factor VEGF-D promotes metastasis by inducing lymphangiogenesis and dilatation of the lymphatic vasculature, facilitating tumor cell extravasion. Here we report a novel level of control for VEGF-D expression at the level of protein translation. In human tumor cells, VEGF-D colocalized with eIF4GI and 4E-BP1, which can program increased initiation at IRES motifs on mRNA by the translational initiation complex. In murine tumors, the steady-state level of VEGF-D protein was increased despite the overexpression and dephosphorylation of 4E-BP1, which downregulates protein synthesis, suggesting the presence of an internal ribosome entry site (IRES) in the 5′ UTR of VEGF-D mRNA. We found that nucleolin, a nucleolar protein involved in ribosomal maturation, bound directly to the 5′UTR of VEGF-D mRNA, thereby improving its translation following heat shock stress via IRES activation. Nucleolin blockade by RNAi-mediated silencing or pharmacologic inhibition reduced VEGF-D translation along with a subsequent constriction of lymphatic vessels in tumors. Our results identify nucleolin as a key regulator of VEGF-D expression, deepening understanding of lymphangiogenesis control during tumor formation. Cancer Res; 76(15); 4394–405. ©2016 AACR.
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- 2016
39. Implication of NPM1 phosphorylation and preclinical evaluation of the nucleoprotein antagonist N6L in prostate cancer
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Francis Vacherot, Charles Marchand, Jocelyn Céraline, Damien Destouches, Fannie Semprez, José Courty, Gilles Carpentier, Pascale Maillé, Pascale Soyeux, Stéphane Terry, Yves Allory, Maha Sader, Alexandre de la Taille, Croissance cellulaire, réparation et régénération tissulaires (CRRET), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Oncogénèse des tumeurs respiratoires et urogénitales, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Altération génétique des cancers, chimioprévention et réponse thérapeutique, Laboratoire CRRET, EAC/CNRS-7149, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service d'urologie [Mondor], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)
- Subjects
Male ,Threonine ,0301 basic medicine ,Angiogenesis ,Docetaxel ,urologic and male genital diseases ,Prostate cancer ,0302 clinical medicine ,Prostate ,androgen receptor ,Medicine ,Phosphorylation ,ComputingMilieux_MISCELLANEOUS ,N6L ,Nuclear Proteins ,prostate cancer ,phosphorylated NPM1 ,Tumor Burden ,3. Good health ,Prostatic Neoplasms, Castration-Resistant ,medicine.anatomical_structure ,Oncology ,Receptors, Androgen ,030220 oncology & carcinogenesis ,Taxoids ,NPM1 ,Nucleophosmin ,Protein Binding ,Research Paper ,medicine.drug ,Mice, Nude ,Antineoplastic Agents ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,03 medical and health sciences ,In vivo ,Cell Line, Tumor ,Animals ,Humans ,business.industry ,Prostatic Neoplasms ,medicine.disease ,Xenograft Model Antitumor Assays ,Androgen receptor ,Nucleoproteins ,030104 developmental biology ,Immunology ,Cancer research ,Peptides ,business - Abstract
Despite the advent of several new treatment options over the past years, advanced/metastatic prostate carcinoma (PCa) still remains incurable, which justifies the search for novel targets and therapeutic molecules. Nucleophosmin (NPM1) is a shuttling nucleoprotein involved in tumor growth and its targeting could be a potential approach for cancer therapy. We previously demonstrated that the multivalent pseudopeptide N6L binds to NPM1 potently affecting in vitro and in vivo tumor cell growth of various tumor types as well as angiogenesis. Furthermore, NPM1 binds to androgen receptor (AR) and modulate its activity. In this study, we first investigated the implication of the NPM1 and its Thr199 and Thr234/237 phosphorylated forms in PCa. We showed that phosphorylated forms of NPM1 interact with androgen receptor (AR) in nucleoplasm. N6L treatment of prostate tumor cells led to inhibition of NPM1 phosphorylation in conjunction with inhibition of AR activity. We also found that total and phosphorylated NPM1 were overexpressed in castration-resistant PCa. Assessment of the potential therapeutic role of N6L in PCa indicated that N6L inhibited tumor growth both in vitro and in vivo when used either alone or in combination with the standard-of-care first- (hormonotherapy) and second-line (docetaxel) treatments for advanced PCa. Our findings reveal the role of Thr199 and Thr234/237 phosphorylated NPM1 in PCa progression and define N6L as a new drug candidate for PCa therapy.
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- 2016
40. Nucleolin antagonist triggers autophagic cell death in human glioblastoma primary cells and decreased in vivo tumor growth in orthotopic brain tumor model
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Benedetta Cinque, Annamaria Cimini, Rodolfo Ippoliti, José Courty, Anne Chloe Dhez, Loredana Cristiano, Michele d'Angelo, Andrea Antonosante, Floriana Rosati, Renato Galzio, Antonio Giordano, Damien Destouches, Alessia Fidoamore, Carlo Astarita, T. Florio, Elisabetta Benedetti, Maria Grazia Cifone, Croissance cellulaire, réparation et régénération tissulaires (CRRET), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Dipartimento di Biologia di Base ed Applicata, Università degli Studi dell'Aquila (UNIVAQ), Laboratoire CRRET, EAC/CNRS-7149, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), and Università degli Studi dell'Aquila = University of L'Aquila (UNIVAQ)
- Subjects
Pathology ,medicine.medical_treatment ,Nude ,Autophagy ,Glioblastoma ,Targeted therapy ,Oncology ,Kaplan-Meier Estimate ,Mice ,0302 clinical medicine ,Tumor Cells, Cultured ,Inbred BALB C ,ComputingMilieux_MISCELLANEOUS ,Microscopy ,0303 health sciences ,Mice, Inbred BALB C ,Tumor ,Cultured ,Brain Neoplasms ,RNA-Binding Proteins ,Drug Synergism ,Middle Aged ,targeted therapy ,Alkylating ,Tumor Cells ,3. Good health ,Tumor Burden ,Dacarbazine ,030220 oncology & carcinogenesis ,Female ,Research Paper ,Adult ,Programmed cell death ,medicine.medical_specialty ,autophagy ,Cell Survival ,Brain tumor ,Mice, Nude ,Antineoplastic Agents ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Aged ,Animals ,Antineoplastic Agents, Alkylating ,Cell Line, Tumor ,Cell Proliferation ,G1 Phase Cell Cycle Checkpoints ,Humans ,Microscopy, Fluorescence ,Peptides ,Phosphoproteins ,Xenograft Model Antitumor Assays ,Biology ,Fluorescence ,Cell Line ,03 medical and health sciences ,Cyclin D1 ,In vivo ,medicine ,Temozolomide ,glioblastoma ,030304 developmental biology ,Cell growth ,medicine.disease ,Cancer research ,Nucleolin - Abstract
Nucleolin (NCL) is highly expressed in several types of cancer and represents an interesting therapeutic target. It is expressed at the plasma membrane of tumor cells, a property which is being used as a marker for several human cancer including glioblastoma. In this study we investigated targeting NCL as a new therapeutic strategy for the treatment of this pathology. To explore this possibility, we studied the effect of an antagonist of NCL, the multivalent pseudopeptide N6L using primary culture of human glioblastoma cells. In this system, N6L inhibits cell growth with different sensitivity depending to NCL localization. Cell cycle analysis indicated that N6L-induced growth reduction was due to a block of the G1/S transition with down-regulation of the expression of cyclin D1 and B2. By monitoring autophagy markers such as p62 and LC3II, we demonstrate that autophagy is enhanced after N6L treatment. In addition, N6L-treatment of mice bearing tumor decreased in vivo tumor growth in orthotopic brain tumor model and increase mice survival. The results obtained indicated an anti-proliferative and pro-autophagic effect of N6L and point towards its possible use as adjuvant agent to the standard therapeutic protocols presently utilized for glioblastoma.
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- 2015
41. Chemotherapeutic Drug Functionalized Nanoparticles are Beneficial When Treating Breast Cancer Via Magnetic Hyperthermia
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Ingrid Hilger, Rodolfo Miranda, Alfonso Latorre, Julia Göring, José Courty, Pierre Couleaud, Álvaro Somoza, Aitziber L. Cortajarena, Julia Grandke, Susann Piehler, Heidi Dähring, and Antonio Aires
- Subjects
Magnetic hyperthermia ,Functionalized nanoparticles ,Breast cancer ,business.industry ,biophysics ,Cancer research ,polycyclic compounds ,Medicine ,Chemotherapeutic drugs ,business ,medicine.disease ,3. Good health - Abstract
Doxorubicin (DOX) is a frequently used chemotherapeutic drug for breast cancer, but its site specificity and local internalization into tumor cells is rather low. In this paper we conjugated magnetic nanoparticles (MNPs) with DOX and/or a pseudopeptide NucAnt (N6L) as modality to enhance DOX-induced antitumor effects in breast cancer cells (BT474). In this context, we determined cellular uptake of MNP formulations, analyzed cell viability and expression of apoptotic and cell cycle proteins after magnetic hyperthermia (43°C, 1 h) in vivo and in vitro. We have shown that i) the presence of N6L on the surface of DOX-functionalized MNPs increases their internalization into a target cells and potentiates the cytotoxic potential of the anticancer drug, ii) in combination with hyperthermia, DOX functionalized MNPs influence the expression of apoptotic and cell cycle proteins, and also favors tumor regression in vivo. Our data show that intratumoral application of DOX coupled MNPs is able to overcome biological barriers to chemotherapeutic drugs, enabling them to penetrate into the target cells. Combined with hyperthermia these MNPs can be an effective method in enhancing the localised delivery and penetration of DOX into breast cancer cells.
- Published
- 2018
42. Targeted therapy of human glioblastoma via delivery of a toxin through a peptide directed to cell surface nucleolin
- Author
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Loredana Cristiano, Andrea Antonosante, Renato Galzio, Anne Chloe Dhez, Marina Melone, Elisabetta Benedetti, Luana Di Leandro, Luca Federici, Michele d'Angelo, Francesco Angelucci, Annamaria Cimini, Gloria Panella, Fabio Raineri, José Courty, T. Florio, Francesco Giansanti, Rodolfo Ippoliti, Antonella De Cola, Ilaria Cascone, Brigida Ranieri, Antonio Giordano, Department of Biochemical Sciences 'Rossi Fanelli', Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Dipartimento di Biologia di Base e Applicata, Università degli Studi dell'Aquila (UNIVAQ), Dipartimento Sci Biochim, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Croissance cellulaire, réparation et régénération tissulaires (CRRET), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Laboratoire CRRET, EAC/CNRS-7149, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Dipartimento di Biologia di Base ed Applicata, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Università degli Studi dell'Aquila = University of L'Aquila (UNIVAQ), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Dhez, A, Benedetti, E, Antonosante, A, Panella, G, Ranieri, B, Florio, T, Cristiano, L, Angelucci, F, Giansanti, F, Di Leandro, L, D'Angelo, M, Melone, Ma, De Cola, A, Federici, L, Galzio, R, Cascone, I, Raineri, F, Cimini, A, Courty, J, Giordano, A, and Ippoliti, R.
- Subjects
0301 basic medicine ,glioblastoma ,NucAnt (N6L) ,nucleolin ,saporin ,targeted therapy ,Physiology ,Clinical Biochemistry ,Cell Biology ,Saporin ,medicine.medical_treatment ,media_common.quotation_subject ,Cell ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Biology ,Targeted therapy ,Mice ,03 medical and health sciences ,0302 clinical medicine ,In vivo ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Molecular Targeted Therapy ,Internalization ,ComputingMilieux_MISCELLANEOUS ,Cell Proliferation ,media_common ,Neovascularization, Pathologic ,Cell Membrane ,RNA-Binding Proteins ,Phosphoproteins ,Saporins ,Xenograft Model Antitumor Assays ,Molecular biology ,Nucleolin ,In vitro ,3. Good health ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,biology.protein ,Peptides - Abstract
Targeted anticancer therapies demand discovery of new cellular targets to be exploited for the delivery of toxic molecules and drugs. In this perspective, in the last few years, nucleolin has been identified as an interesting surface marker to be used for the therapy of glioblastoma. In this study, we investigated whether a synthetic antagonist of cell-surface nucleolin known as N6L, previously reported to decrease both tumour growth and tumour angiogenesis in several cancer cell lines, including glioblastoma cells, as well as endothelial cells proliferation, could be exploited to deliver a protein toxin (saporin) to glioblastoma cells. The pseudopeptide N6L cross-linked to saporin-S6 induced internalization of the toxin inside glioblastoma cancer cells. Our results in vitro demonstrated the effectiveness of this conjugate in inducing cell death, with an ID50 four orders of magnitude lower than that observed for free N6L. Furthermore, the preliminary "in vivo" study demonstrated efficiency in reducing the tumour mass in an orthotopic mouse model of glioblastoma
- Published
- 2018
43. Evidence for Novel Action at the Cell-Binding Site of Human Angiogenin Revealed by Heteronuclear NMR Spectroscopy, in silico and in vivo Studies
- Author
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José Courty, Josette Badet, Dimitri Komiotis, Aikaterini C. Tsika, Vassiliki T. Skamnaki, Joseph Hayes, Vanessa Parmenopoulou, Demetra S.M. Chatzileontiadou, Zoi Diamantopoulou, Georgios A. Spyroulias, Jean Delbé, Demetres D. Leonidas, Croissance cellulaire, réparation et régénération tissulaires (CRRET), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Développement humain : Croissance et différenciation, Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire CRRET, EAC/CNRS-7149, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Department of Pharmacy, University of Patras [Greece], Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and University of Patras [Patras]
- Subjects
0301 basic medicine ,Angiogenin ,RNase P ,[SDV]Life Sciences [q-bio] ,Neovascularization, Physiologic ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Chick Embryo ,Molecular Dynamics Simulation ,Biochemistry ,Chorioallantoic Membrane ,Cell Line ,03 medical and health sciences ,Structure-Activity Relationship ,0302 clinical medicine ,In vivo ,Drug Discovery ,Animals ,Humans ,Computer Simulation ,General Pharmacology, Toxicology and Pharmaceutics ,Nuclear Magnetic Resonance, Biomolecular ,ComputingMilieux_MISCELLANEOUS ,Pharmacology ,Binding Sites ,biology ,Chemistry ,Organic Chemistry ,Active site ,Nucleoside inhibitor ,Nuclear magnetic resonance spectroscopy ,Ribonuclease, Pancreatic ,Pyrimidine Nucleosides ,3. Good health ,030104 developmental biology ,Heteronuclear molecule ,Docking (molecular) ,030220 oncology & carcinogenesis ,biology.protein ,Biophysics ,Molecular Medicine - Abstract
A member of the ribonuclease A superfamily, human angiogenin (hAng) is a potent angiogenic factor. Heteronuclear NMR spectroscopy combined with induced-fit docking revealed a dual binding mode for the most antiangiogenic compound of a series of ribofuranosyl pyrimidine nucleosides that strongly inhibit hAng's angiogenic activity in vivo. While modeling suggests the potential for simultaneous binding of the inhibitors at the active and cell-binding sites, NMR studies indicate greater affinity for the cell-binding site than for the active site. Additionally, molecular dynamics simulations at 100 ns confirmed the stability of binding at the cell-binding site with the predicted protein-ligand interactions, in excellent agreement with the NMR data. This is the first time that a nucleoside inhibitor is reported to completely inhibit the angiogenic activity of hAng in vivo by exerting dual inhibitory activity on hAng, blocking both the entrance of hAng into the cell and its ribonucleolytic activity.
- Published
- 2017
44. Pleiotrophin Exerts Its Migration and Invasion Effect through the Neuropilin-1 Pathway
- Author
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Yamina Hamma-Kourbali, Charly Blanc, Sophie Frechault, Ilaria Cascone, Gilles Carpentier, Damien Destouches, José Courty, Jean Delbé, Rania Elahouel, Croissance cellulaire, réparation et régénération tissulaires (CRRET), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Laboratoire CRRET, EAC/CNRS-7149, and Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)
- Subjects
Cancer Research ,Angiogenesis ,Recombinant Fusion Proteins ,medicine.medical_treatment ,Immunoblotting ,CHO Cells ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Biology ,Pleiotrophin ,lcsh:RC254-282 ,Article ,Focal adhesion ,Cricetulus ,Cell Movement ,Cell Line, Tumor ,Cricetinae ,[SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB] ,Neuropilin 1 ,medicine ,Animals ,Humans ,Neoplasm Invasiveness ,Cells, Cultured ,ComputingMilieux_MISCELLANEOUS ,Glutathione Transferase ,Binding Sites ,Growth factor ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Endocytosis ,Neuropilin-1 ,3. Good health ,Cell biology ,Microscopy, Fluorescence ,Tumor progression ,Cancer research ,Cytokines ,RNA Interference ,Human umbilical vein endothelial cell ,Signal transduction ,Carrier Proteins ,Protein Binding ,Signal Transduction - Abstract
Pleiotrophin (PTN) is a pleiotropic growth factor that exhibits angiogenic properties and is involved in tumor growth and metastasis. Although it has been shown that PTN is expressed in tumor cells, few studies have investigated its receptors and their involvement in cell migration and invasion. Neuropilin-1 (NRP-1) is a receptor for multiple growth factors that mediates cell motility and plays an important role in angiogenesis and tumor progression. Here we provide evidence for the first time that NRP-1 is crucial for biological activities of PTN. We found that PTN interacted directly with NRP-1 through its thrombospondin type-I repeat domains. Importantly, binding of PTN to NRP-1 stimulated the internalization and recycling of NRP-1 at the cell surface. Invalidation of NRP-1 by RNA interference in human carcinoma cells inhibited PTN-induced intracellular signaling of the serine-threonine kinase, mitogen-activated protein MAP kinase, and focal adhesion kinase pathways. Accordingly, NRP-1 silencing or blocking by antibody inhibited PTN-induced human umbilical vein endothelial cell migration and tumor cell invasion. These results suggest that NRP-1/PTN interaction provides a novel mechanism for controlling the response of endothelial and tumoral cells to PTN and may explain, at least in part, how PTN contributes to tumor angiogenesis and cancer progression.
- Published
- 2015
45. N6L pseudopeptide interferes with nucleophosmin protein-protein interactions and sensitizes leukemic cells to chemotherapy
- Author
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A. Di Matteo, Luca Federici, Ilaria Cascone, Rodolfo Ippoliti, E. Clemente, Maria Angela Franceschini, Annamaria Cimini, Damien Destouches, R. Celani, Anne Chloe Dhez, F. Raineri, Benoit Vallée, José Courty, Gianni Colotti, V De Laurenzi, A De Cola, STMicroelectronics, Department of Health, Life and Environmental Sciences, Università degli Studi dell'Aquila (UNIVAQ), Laboratoire de photonique et de nanostructures (LPN), Centre National de la Recherche Scientifique (CNRS), Department of Experimental Medicine and Biochemical Sciences, IDI,IRCCS, Biochemistry Laboratory, Università degli Studi di Roma Tor Vergata [Roma], Laboratoire CRRET, EAC/CNRS-7149, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Croissance cellulaire, réparation et régénération tissulaires (CRRET), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Service de médecine interne diabète et maladies métaboliqe, Hôpital civil Strasbourg, and Università degli Studi dell'Aquila = University of L'Aquila (UNIVAQ)
- Subjects
0301 basic medicine ,Cancer Research ,NPM1 ,DNA damage ,[SDV]Life Sciences [q-bio] ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Biology ,Targeted therapy ,03 medical and health sciences ,Cell Line, Tumor ,medicine ,Humans ,ComputingMilieux_MISCELLANEOUS ,Nucleophosmin ,Acute myeloid leukemia ,Cell growth ,RUNX1T1 ,Cytarabine ,Myeloid leukemia ,Nuclear Proteins ,NPM1 mutations ,3. Good health ,Leukemia, Myeloid, Acute ,030104 developmental biology ,Oncology ,Doxorubicin ,Mutation ,Cancer research ,Tumor Suppressor Protein p53 ,Peptides ,Nucleolin ,medicine.drug - Abstract
NPM1 is a multifunctional nucleolar protein implicated in several processes such as ribosome maturation and export, DNA damage response and apoptotic response to stress stimuli. The NPM1 gene is involved in human tumorigenesis and is found mutated in one third of acute myeloid leukemia patients, leading to the aberrant cytoplasmic localization of NPM1. Recent studies indicated that the N6L multivalent pseudopeptide, a synthetic ligand of cell-surface nucleolin, is also able to bind NPM1 with high affinity. N6L inhibits cell growth with different mechanisms and represents a good candidate as a novel anticancer drug for a number of malignancies of different histological origin. In this study we investigated whether N6L treatment could drive antitumor effect in acute myeloid leukemia cell lines. We found that N6L binds NPM1 at the N-terminal domain, co-localizes with cytoplasmic, mutated NPM1, and interferes with its protein-protein associations. N6L toxicity appears to be p53 dependent but interestingly, the leukemic cell line harbouring the mutated form of NPM1 is more resistant to treatment, suggesting that NPM1 cytoplasmic delocalization confers protection from p53 activation. Moreover, we show that N6L sensitizes AML cells to doxorubicin and cytarabine treatment. These studies suggest that N6L may be a promising option in combination therapies for acute myeloid leukemia treatment.
- Published
- 2017
46. Cell Colonization Ability of a Commercialized Large Porous Alveolar Scaffold
- Author
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José Courty, Nathalie Chevallier, Thibault Lemaire, Hélène Rouard, Thibault Bouderlique, S. Lemonnier, Salah Naili, Patricia Albanese, Laboratoire de Modélisation et Simulation Multi Echelle (MSME), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Université Paris-Est Marne-la-Vallée (UPEM), Croissance cellulaire, réparation et régénération tissulaires (CRRET), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Unité d’Ingénierie et de thérapie cellulaire, Etablissement Français du Sang, Biomécanique cellulaire et respiratoire (BCR), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), EAC 7149, Laboratoire de Modélisation et Simulation Multi Echelle ( MSME ), Université Paris-Est Marne-la-Vallée ( UPEM ) -Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de recherche sur la croissance cellulaire, la réparation et la régénération tissulaires ( CRRET ), Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ) -Centre National de la Recherche Scientifique ( CNRS ), Biomécanique cellulaire et respiratoire ( BCR ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ) -Centre National de la Recherche Scientifique ( CNRS ), and Université Paris-Est Marne-la-Vallée (UPEM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Scaffold ,Article Subject ,QH301-705.5 ,0206 medical engineering ,Cell ,Biomedical Engineering ,Medicine (miscellaneous) ,Bioengineering ,02 engineering and technology ,In vivo ,medicine ,Biology (General) ,Porosity ,ComputingMilieux_MISCELLANEOUS ,Chemistry ,Mesenchymal stem cell ,[SPI.MECA.BIOM]Engineering Sciences [physics]/Mechanics [physics.med-ph]/Biomechanics [physics.med-ph] ,021001 nanoscience & nanotechnology ,Biocompatible material ,020601 biomedical engineering ,Porous scaffold ,medicine.anatomical_structure ,Biophysics ,Seeding ,[ SPI.MECA.BIOM ] Engineering Sciences [physics]/Mechanics [physics.med-ph]/Biomechanics [physics.med-ph] ,0210 nano-technology ,TP248.13-248.65 ,Research Article ,Biotechnology - Abstract
The use of filling biomaterials or tissue-engineered large bone implant-coupling biocompatible materials and human bone marrow mesenchymal stromal cells seems to be a promising approach to treat critical-sized bone defects. However, the cellular seeding onto and into large porous scaffolds still remains challenging since this process highly depends on the porous microstructure. Indeed, the cells may mainly colonize the periphery of the scaffold, leaving its volume almost free of cells. In this study, we carry out an in vitro study to analyze the ability of a commercialized scaffold to be in vivo colonized by cells. We investigate the influence of various physical parameters on the seeding efficiency of a perfusion seeding protocol using large manufactured bone substitutes. The present study shows that the velocity of the perfusion fluid and the initial cell density seem to impact the seeding results and to have a negative effect on the cellular viability, whereas the duration of the fluid perfusion and the nature of the flow (steady versus pulsed) did not show any influence on either the fraction of seeded cells or the cellular viability rate. However, the cellular repartition after seeding remains highly heterogeneous.
- Published
- 2017
47. Expression of the growth factor pleiotrophin and its receptor protein tyrosine phosphatase beta/zeta in the serum, cartilage and subchondral bone of patients with osteoarthritis
- Author
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Lubna Khaldi, Spyridon Dangas, Constantinos M. Mikelis, Frédéric Lioté, I. Kouvaras, Mélanie Héroult, Angelos Kaspiris, Theodoros B Grivas, Elias Vasiliadis, José Courty, and Evangelia Papadimitriou
- Subjects
Adult ,Male ,medicine.medical_specialty ,Arthroplasty, Replacement, Hip ,medicine.medical_treatment ,Osteoarthritis ,Protein tyrosine phosphatase ,Pleiotrophin ,Osteocytes ,Severity of Illness Index ,Bone and Bones ,Osteoarthritis, Hip ,Receptor Protein Tyrosine Phosphatase-beta ,Disability Evaluation ,Chondrocytes ,Rheumatology ,Internal medicine ,Humans ,Medicine ,Arthroplasty, Replacement, Knee ,Aged ,Aged, 80 and over ,Receptor-Like Protein Tyrosine Phosphatases, Class 5 ,business.industry ,Growth factor ,Cartilage ,Middle Aged ,Osteoarthritis, Knee ,medicine.disease ,Embryonic stem cell ,Endocrinology ,medicine.anatomical_structure ,Subchondral bone ,Case-Control Studies ,Cytokines ,Female ,Carrier Proteins ,business ,Biomarkers - Abstract
Objectives Pleiotrophin is a heparin-binding growth factor expressed in embryonic but not mature cartilage, suggesting a role in cartilage development. Elucidation of the molecular changes observed during the remodelling process in osteoarthritis is of paramount importance. This study aimed to investigate serum pleiotrophin levels and expression of pleiotrophin and its receptor protein tyrosine phosphatase beta/zeta in the cartilage and subchondral bone of osteoarthritis patients. Methods Serum samples derived from 16 osteoarthritis patients and 18 healthy donors. Pleiotrophin and receptor protein tyrosine phosphatase beta/zeta in the cartilage and subchondral bone were studied in 29 patients who had undergone total knee or hip replacement for primary osteoarthritis and in 10 control patients without macroscopic osteoarthritis changes. Results Serum pleiotrophin levels and expression of pleiotrophin in chondrocytes and subchondral bone osteocytes significantly increased in osteoarthritis patients graded Ahlback II to III. Receptor protein tyrosine phosphatase beta/zeta was mainly detected in the subchondral bone osteocytes of patients with moderate osteoarthritis and as disease severity increased, in the osteocytes and bone lining cells of the distant trabeculae. Conclusions These data render pleiotrophin and receptor protein tyrosine phosphatase beta/zeta promising candidates for further studies towards developing targeted therapeutic schemes for osteoarthritis.
- Published
- 2013
48. Pleiotrophin promotes capillary-like sprouting from senescent aortic rings
- Author
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Romain Comte, Sophie Frechault, José Courty, de Leiris Joël, Jean Delbé, and Sophie Besse
- Subjects
Male ,Vascular Endothelial Growth Factor A ,Aging ,medicine.medical_specialty ,Angiogenesis ,medicine.medical_treatment ,Immunology ,Neovascularization, Physiologic ,Hindlimb ,In Vitro Techniques ,Pleiotrophin ,Biochemistry ,Neovascularization ,chemistry.chemical_compound ,Internal medicine ,medicine ,Animals ,Humans ,Immunology and Allergy ,Rats, Wistar ,Molecular Biology ,Aorta ,Tube formation ,Chemistry ,Growth factor ,Hematology ,Rats ,Vascular endothelial growth factor ,Endocrinology ,Cytokines ,medicine.symptom ,Carrier Proteins ,Ex vivo - Abstract
Pleiotrophin (PTN) is a heparin-binding growth factor involved in angiogenesis during development and tumor growth. Plasmid therapy with PTN also induces angiogenesis after myocardial infarction. During aging, angiogenesis is impaired and we therefore examined whether a growth factor therapy with PTN is able to restore neovascularization.We evaluated the PTN effects on capillary-like endothelial sprouting in adult (n = 10) and senescent (n = 10) rats, using an ex vivo model of explanted aortic segments in culture. Freshly cut thoracic aortic rings from 3 and 24 month old (mo) rats (both n = 12) were cultured in a 3-dimensional collagen matrix with or without addition of recombinant human PTN (2.5-250 ng/ml) or Vascular Endothelial Growth Factor-165 (VEGF) (1-100 ng/ml) and the length of developed capillary network was quantified at day 3 and 6 by image analysis.After 6 days of culture, capillary-like tube formation was lower in control conditions in 24 mo aortic rings than in 3 mo rings. Addition of PTN increased dose-dependently the length of capillary-like tube formation in both 3 and 24 mo rings (P0.001 and P0.001 respectively). Age-associated impairment of capillary-like tube formation had been successfully restored in senescent aortic segments by PTN treatment. PTN induced development of capillary network similar to that observed with VEGF therapy with doses equal or superior to 10 ng/ml.PTN is able to induce ex vivo angiogenesis during aging and might be a new promising therapy to induce neovascularization in aged tissues as well as after age-associated cardiac, hindlimb or cerebral ischemia.
- Published
- 2013
49. Multivalent Pseudopeptides Targeting Cell Surface Nucleoproteins Inhibit Cancer Cell Invasion through Tissue Inhibitor of Metalloproteinases 3 (TIMP-3) Release
- Author
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Damien Destouches, Sophie Frechault, José Courty, Maha Sader, Jean-Paul Briand, Suzanne Menashi, Eric Huet, Gilles Carpentier, and Florie Ayoul
- Subjects
Angiogenesis ,viruses ,Cell ,Antineoplastic Agents ,Mice, Transgenic ,Biology ,Matrix metalloproteinase ,Biochemistry ,Extracellular matrix ,Mice ,Cell Line, Tumor ,Neoplasms ,medicine ,Animals ,Humans ,Neoplasm Invasiveness ,RNA, Messenger ,RNA, Neoplasm ,Molecular Biology ,Tissue Inhibitor of Metalloproteinase-3 ,Melanoma ,Cell Biology ,medicine.disease ,Molecular biology ,Neoplasm Proteins ,Gene Expression Regulation, Neoplastic ,medicine.anatomical_structure ,Lead ,Cell culture ,Cancer cell ,Cancer research ,Peptides ,Nucleolin - Abstract
Blockage of the metastasis process remains a significant clinical challenge, requiring innovative therapeutic approaches. For this purpose, molecules that inhibit matrix metalloproteinases activity or induce the expression of their natural inhibitor, the tissue inhibitor of metalloproteinases (TIMPs), are potentially interesting. In a previous study, we have shown that synthetic ligands binding to cell surface nucleolin/nucleophosmin and known as HB 19 for the lead compound and NucAnt 6L (N6L) for the most potent analog, inhibit both tumor growth and angiogenesis. Furthermore, they prevent metastasis in a RET transgenic mice model which develops melanoma. Here, we investigated the effect of N6L on the invasion capacity of MDA-MB-435 melanoma cells. Our results show that the multivalent pseudopeptide N6L inhibited Matrigel invasion of MDA-MB-435 cells in a modified Boyden chamber model. This was associated with an increase in TIMP-3 in the cell culture medium without a change in TIMP-3 mRNA expression suggesting its release from cell surface and/or extracellular matrix. This may be explained by our demonstrated N6L interaction with sulfated glycosaminoglycans and consequently the controlled bioavailability of glycosaminoglycan-bound TIMP-3. The implication of TIMP-3 in N6L-induced inhibition of cell invasion was evidenced by siRNA silencing experiments showing that the loss of TIMP-3 expression abrogated the effect of N6L. The inhibition of tumor cell invasion by N6L demonstrated in this study, in addition to its previously established inhibitory effect on tumor growth and angiogenesis, suggests that N6L represents a promising anticancer drug candidate warranting further investigation.
- Published
- 2012
50. Loss of Receptor Protein Tyrosine Phosphatase β/ζ (RPTPβ/ζ) Promotes Prostate Cancer Metastasis
- Author
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José Courty, Zoi Diamantopoulou, Suzanne Menashi, Paraskevi Kitsou, and Panagiotis Katsoris
- Subjects
Male ,animal structures ,Mice, Nude ,Protein tyrosine phosphatase ,medicine.disease_cause ,Pleiotrophin ,Biochemistry ,Mice ,DU145 ,Cell Movement ,Cell Line, Tumor ,medicine ,Animals ,Humans ,PTEN ,Neoplasm Metastasis ,Phosphorylation ,Molecular Biology ,Mice, Knockout ,biology ,Receptor-Like Protein Tyrosine Phosphatases, Class 5 ,Prostatic Neoplasms ,Cell migration ,Cell Biology ,Up-Regulation ,carbohydrates (lipids) ,embryonic structures ,Cancer research ,biology.protein ,Syndecan-3 ,Signal transduction ,Carcinogenesis ,Signal Transduction ,Proto-oncogene tyrosine-protein kinase Src - Abstract
The role of pleiotrophin and its receptors RPTPβ/ζ and Syndecan-3 during tumor metastasis remains unknown.RPTPβ/ζ knockdown initiates EMT, promotes pleiotrophin-mediated migration and attachment through Syndecan-3 and induces in vivo metastasis.RPTPβ/ζ plays a suppressor-like role in prostate cancer metastasis.Boosting RPTPβ/ζ or attenuating Syndecan-3 signaling pathways may lead to more effective therapeutic strategies in treating prostate cancer metastasis. Pleiotrophin is a growth factor that induces carcinogenesis. Despite the fact that many published reports focused on the role of pleiotrophin and its receptors, receptor protein tyrosine phosphatase (RPTPβ/ζ), and syndecan-3 during tumor development, no information is available regarding their function in tumor metastasis. To investigate the mechanism through which pleiotrophin regulates tumor metastasis, we used two different prostate carcinoma cell lines, DU145 and PC3, in which the expression of RPTPβ/ζ or syndecan-3 was down-regulated by the RNAi technology. The loss of RPTPβ/ζ expression initiated epithelial-to-mesenchymal transition (EMT) and increased the ability of the cells to migrate and invade. Importantly, the loss of RPTPβ/ζ expression increased metastasis in nude mice in an experimental metastasis assay. We also demonstrate that RPTPβ/ζ counterbalanced the pleiotrophin-mediated syndecan-3 pathway. While the inhibition of syndecan-3 expression inhibited the pleiotrophin-mediated cell migration and attachment through the Src and Fak pathway, the inhibition of RPTPβ/ζ expression increased pleiotrophin-mediated migration and attachment through an interaction with Src and the subsequent activation of a signal transduction pathway involving Fak, Pten, and Erk1/2. Taken together, these results suggest that the loss of RPTPβ/ζ may contribute to the metastasis of prostate cancer cells by inducing EMT and promoting pleiotrophin activity through the syndecan-3 pathway.
- Published
- 2012
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