title: Multivalent DR5 peptides activate the TRAIL death pathway and exert tumoricidal activity.
abstract: Ongoing clinical trials are exploring anticancer approaches based on signaling by TRAIL, a ligand for the cell death receptors DR4 and DR5. In this study, we report on the selective apoptotic effects of multivalent DR5 binding peptides (TRAIL(mim/DR5)) on cancer cells in vitro and in vivo. Surface plasmon resonance revealed up to several thousand-fold increased affinities of TRAIL(mim/DR5)-receptor complexes on generation of divalent and trivalent molecules, the latter of which was achieved with a conformationally restricted adamantane core. Notably, only multivalent molecules triggered a substantial DR5-dependent apoptotic response in vitro. In tumor models derived from human embryonic kidney cells or primary foreskin fibroblasts, TRAIL(mim/DR5) peptides exerted a cancer cell-selective action that could synergize with resveratrol in a manner independent of p53. In a xenograft model of human colon cancer, a divalent TRAIL(mim/DR5) peptide inhibited tumor growth. Our results offer a proof-of-principle for the development of synthetic small molecules to trigger the TRAIL apoptosis pathway for cancer therapy.
authors.affiliation: Department of Cancer Biology, Institut de Génétique et de Biologie Moléculaire et Cellulaire, BP 10142, Illkirch, France.
authors.forename: Valeria
authors.initials: V
authors.lastname: Pavet
authors.forename: Julien
authors.initials: J
authors.lastname: Beyrath
authors.forename: Christophe
authors.initials: C
authors.lastname: Pardin
authors.forename: Alexandre
authors.initials: A
authors.lastname: Morizot
authors.forename: Marie-Charlotte
authors.initials: MC
authors.lastname: Lechner
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Briand
authors.forename: Miriam
authors.initials: M
authors.lastname: Wendland
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Maison
authors.forename: Sylvie
authors.initials: S
authors.lastname: Fournel
authors.forename: Olivier
authors.initials: O
authors.lastname: Micheau
authors.forename: Gilles
authors.initials: G
authors.lastname: Guichard
authors.forename: Hinrich
authors.initials: H
authors.lastname: Gronemeyer
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D004357:Drug Synergism; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000737:chemistry / Q000378:metabolism; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects*; D013267:Stilbenes / Q000494:pharmacology; D020349:Surface Plasmon Resonance; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D009842:Oligopeptides; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D013267:Stilbenes; D053221:TNF-Related Apoptosis-Inducing Ligand; D000077185:Resveratrol