1. A Simple Approach to Cancer Therapy Afforded by Multivalent Pseudopeptides That Target Cell-Surface Nucleoproteins
- Author
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Sophie Frechault, Nicolas Page, Dominique Bagnard, Charalampos Birmpas, Alain Van Dorsselaer, Julien Beyrath, Patricia Albanese, José Courty, Gilles Carpentier, Jean Marc Strub, Sylvianne Muller, Marie Maurer, Yamina Hamma-Kourbali, Damien Destouches, Valerie Machi, Panagiotis Katsoris, Olivier Chaloin, Jean-Paul Briand, 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), Immunologie et chimie thérapeutiques (ICT), Cancéropôle du Grand Est-Centre National de la Recherche Scientifique (CNRS), Department of Pharmacy, University of Patras [Patras], Ecole Nationale Vétérinaire Maisons-Alfort, École nationale vétérinaire - Alfort (ENVA), Laboratoire de Spectrométrie de Masse BioOrganique [Strasbourg] (LSMBO), Département Sciences Analytiques et Interactions Ioniques et Biomoléculaires (DSA-IPHC), Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie du système nerveux., Université Louis Pasteur - Strasbourg I-IFR37-Institut National de la Santé et de la Recherche Médicale (INSERM), This research was funded by the CNRS, the Région Alsace, La Ligue contre le Cancer, and the Ministère de l'Enseignement Supérieur et de la Recherche., University of Patras [Greece], Laboratoire de Spectrométrie de Masse BioOrganique (IPHC-DSA), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut Pluridisciplinaire Hubert Curien (IPHC), and Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Cancer Research ,Lymphoma ,Cell Survival ,Angiogenesis ,Cell ,Membrane transport and intracellular motility [NCMLS 5] ,Apoptosis ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Cell Growth Processes ,Biology ,Ligands ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Annexin ,In vivo ,Cell Line, Tumor ,Neoplasms ,medicine ,Animals ,Humans ,cancer ,Tissue Distribution ,Molecular Targeted Therapy ,030304 developmental biology ,Mice, Inbred BALB C ,therapy ,0303 health sciences ,Endothelial Cells ,RNA-Binding Proteins ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,Phosphoproteins ,Xenograft Model Antitumor Assays ,In vitro ,3. Good health ,Mice, Inbred C57BL ,Mitochondrial medicine Membrane transport and intracellular motility [IGMD 8] ,medicine.anatomical_structure ,Oncology ,Cell culture ,030220 oncology & carcinogenesis ,Immunology ,Cancer research ,DNA fragmentation ,Peptides ,Nucleolin ,Cell Nucleolus ,multivalent pseudopeptide - Abstract
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.
- Published
- 2011