title: Anticancer copper(II) phosphorus dendrimers are potent proapoptotic Bax activators.
abstract: A multivalent phosphorus dendrimer 1G3and its corresponding Cu-complex, 1G3-Cu have been recently identified as agents retaining high antiproliferative potency. This antiproliferative capacity was preserved in cell lines overexpressing the efflux pump ABC B1, whereas cross-resistance was observed in ovarian cancer cell lines resistant to cisplatin. Theoretical 3D models were constructed: the dendrimers appear as irregularly shaped disk-like nano-objects of about 22 Å thickness and 49 Å diameter, which accumulated in cells after penetration by endocytosis. To get insight in their mode of action, cell death pathways have been examined in human cancer cell lines: early apoptosis was followed by secondary necrosis after multivalent phosphorus dendrimers exposure. The multivalent plain phosphorus dendrimer 1G3moderately activated caspase-3 activity, in contrast with the multivalent Cu-conjugated phosphorus dendrimer 1G3-Cu which strikingly reduced the caspase-3 content and activity. This decrease of caspase activity is not related to the presence of copper, since inorganic copper has no or little effect on caspase-3. Conversely the potent apoptosis activation could be related to a noticeable translocation of Bax to the mitochondria, resulting in the release of AIF into the cytosol, its translocation to the nucleus and a severe DNA fragmentation, without alteration of the cell cycle. The multivalent Cu-conjugated phosphorus dendrimer is more efficient than its non-complexed analog to activate this pathway in close relationship with the higher antiproliferative potency. Therefore, this multivalent Cu-conjugated phosphorus dendrimer 1G3-Cu can be considered as a new and promising first-in-class antiproliferative agent with a distinctive mode of action, inducing apoptosis tumor cell death through Bax activation pathway.
authors.affiliation: Université Paris Descartes, PRES Sorbonne Paris Cité, CNRS UMR 860, Laboratoire de Chimie et de Biochimie pharmacologiques et toxicologiques, 45, rue des Saints Pères, 75006 Paris, France. Electronic address: serge.mignani@parisdescartes.fr.
authors.forename: Serge
authors.initials: S
authors.lastname: Mignani
authors.affiliation: Euromed Research Institute, Euro-Mediterranean University of Fes (UEMF), Route de Meknes, 30000, Fès, Morocco; Laboratoire de Chimie de Coordination du CNRS, 205 route de Narbonne, 31077 Toulouse Cedex 4, France; Université de Toulouse UPS, INPT, F 31077 Toulouse Cedex 4, France.
authors.forename: Nabil
authors.initials: N
authors.lastname: El Brahmi
authors.affiliation: ICSN-CNRS UPR 2301, Avenue de la Terrasse, 91198 Gif sur Yvette, France.
authors.forename: Laure
authors.initials: L
authors.lastname: Eloy
authors.affiliation: Laboratoire de Toxicologie Biologique, Hôpital Lariboisière, 75475 Paris Cedex 10, France.
authors.forename: Joel
authors.initials: J
authors.lastname: Poupon
authors.affiliation: IPSIT, Faculté de Pharmacie, Université Paris Sud, 92290 Chatenay-Malabry, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Nicolas
authors.affiliation: Sanofi R&D, LGCR, Centre de Recherche Vitry-Alfortville, 94403 Vitry-sur-Seine Cedex, France.
authors.forename: Anke
authors.initials: A
authors.lastname: Steinmetz
authors.affiliation: Euromed Research Institute, Euro-Mediterranean University of Fes (UEMF), Route de Meknes, 30000, Fès, Morocco.
authors.forename: Said
authors.initials: S
authors.lastname: El Kazzouli
authors.affiliation: Euromed Research Institute, Euro-Mediterranean University of Fes (UEMF), Route de Meknes, 30000, Fès, Morocco.
authors.forename: Mosto M
authors.initials: MM
authors.lastname: Bousmina
authors.affiliation: Institut des Sciences Moléculaires, UMR 5255, Université de Bordeaux, 351 cours de la Libération, Talence, France.
authors.forename: Mireille
authors.initials: M
authors.lastname: Blanchard-Desce
authors.affiliation: Laboratoire de Chimie de Coordination du CNRS, 205 route de Narbonne, 31077 Toulouse Cedex 4, France; Université de Toulouse UPS, INPT, F 31077 Toulouse Cedex 4, France.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Caminade
authors.affiliation: Laboratoire de Chimie de Coordination du CNRS, 205 route de Narbonne, 31077 Toulouse Cedex 4, France; Université de Toulouse UPS, INPT, F 31077 Toulouse Cedex 4, France. Electronic address: majoral@lcc-toulouse.fr.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Majoral
authors.affiliation: ICSN-CNRS UPR 2301, Avenue de la Terrasse, 91198 Gif sur Yvette, France; IPSIT, Faculté de Pharmacie, Université Paris Sud, 92290 Chatenay-Malabry, France. Electronic address: thierry.cresteil@u-psud.fr.
authors.forename: Thierry
authors.initials: T
authors.lastname: Cresteil
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001693:Biological Transport, Active / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D003300:Copper / Q000737:chemistry; D050091:Dendrimers / Q000737:chemistry* / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D015394:Molecular Structure; D010758:Phosphorus / Q000737:chemistry; D051028:bcl-2-Associated X Protein / Q000187:drug effects* / Q000378:metabolism
chemical_list: D050091:Dendrimers; D051028:bcl-2-Associated X Protein; D010758:Phosphorus; D003300:Copper; C505407:CASP3 protein, human; D053148:Caspase 3
keywords: Apoptosis; Bax translocation; Dendrimers; Nanomedicine; Oncology