title: Highly efficient radiosensitization of human glioblastoma and lung cancer cells by a G-quadruplex DNA binding compound.
abstract: Telomeres are nucleoprotein structures at the end of chromosomes which stabilize and protect them from nucleotidic degradation and end-to-end fusions. The G-rich telomeric single-stranded DNA overhang can adopt a four-stranded G-quadruplex DNA structure (G4). Stabilization of the G4 structure by binding of small molecule ligands enhances radiosensitivity of tumor cells, and this combined treatment represents a novel anticancer approach. We studied the effect of the platinum-derived G4-ligand, Pt-ctpy, in association with radiation on human glioblastoma (SF763 and SF767) and non-small cell lung cancer (A549 and H1299) cells in vitro and in vivo. Treatments with submicromolar concentrations of Pt-ctpy inhibited tumor proliferation in vitro with cell cycle alterations and induction of apoptosis. Non-toxic concentrations of the ligand were then combined with ionizing radiation. Pt-ctpy radiosensitized all cell lines with dose-enhancement factors between 1.32 and 1.77. The combined treatment led to increased DNA breaks. Furthermore, a significant radiosensitizing effect of Pt-ctpy in mice xenografted with glioblastoma SF763 cells was shown by delayed tumor growth and improved survival. Pt-ctpy can act in synergy with radiation for efficient killing of cancer cells at concentrations at which it has no obvious toxicity per se, opening perspectives for future therapeutic applications.
authors.affiliation: Clermont Université, Université d'Auvergne, EA 7283, 63003 Clermont-Ferrand, France.|CHU Clermont-Ferrand, Service de Pneumologie Oncologie Thoracique, 63003 Clermont-Ferrand, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Merle
authors.affiliation: Clermont Université, Université d'Auvergne, EA 7283, 63003 Clermont-Ferrand, France.
authors.forename: Marine
authors.initials: M
authors.lastname: Gueugneau
authors.affiliation: Institut Curie, UMR 176, Centre Universitaire Paris-Sud, 91405 Orsay, France.
authors.forename: Marie-Paule
authors.initials: MP
authors.lastname: Teulade-Fichou
authors.affiliation: Clermont Université, Université d'Auvergne, EA 7283, 63003 Clermont-Ferrand, France.|Centre Jean Perrin, Département de Radiothérapie, 63011 Clermont-Ferrand, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Müller-Barthélémy
authors.affiliation: Génétique, Reproduction et Développement, UMR CNRS 6293, Clermont Université, INSERM U1103, 63170 Aubière, France.
authors.forename: Simon
authors.initials: S
authors.lastname: Amiard
authors.affiliation: Clermont Université, Université d'Auvergne, EA 7283, 63003 Clermont-Ferrand, France.|Centre Jean Perrin, Département de Radiothérapie, 63011 Clermont-Ferrand, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Chautard
authors.affiliation: Institut Curie, UMR 176, Centre Universitaire Paris-Sud, 91405 Orsay, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Guetta
authors.affiliation: Clermont Université, Université d'Auvergne, EA 7283, 63003 Clermont-Ferrand, France.|Centre Jean Perrin, Département de Radiothérapie, 63011 Clermont-Ferrand, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Dedieu
authors.affiliation: Centre Jean Perrin, Laboratoire OncoGènAuvergne, 63011 Clermont-Ferrand, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Communal
authors.affiliation: Université de Bordeaux, 33076 Bordeaux, France.|INSERM U1212, ARNA laboratory, IECB, 33607 Pessac, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Mergny
authors.affiliation: Génétique, Reproduction et Développement, UMR CNRS 6293, Clermont Université, INSERM U1103, 63170 Aubière, France.
authors.forename: Maria
authors.initials: M
authors.lastname: Gallego
authors.affiliation: Génétique, Reproduction et Développement, UMR CNRS 6293, Clermont Université, INSERM U1103, 63170 Aubière, France.
authors.forename: Charles
authors.initials: C
authors.lastname: White
authors.affiliation: Clermont Université, Université d'Auvergne, EA 7283, 63003 Clermont-Ferrand, France.|Département de Radiothérapie, Institut Curie, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Verrelle
authors.affiliation: Clermont Université, Université d'Auvergne, EA 7283, 63003 Clermont-Ferrand, France.|Clermont Université, Université d'Auvergne, Histologie Embryologie Cytogénétique, 63001 Clermont-Ferrand, France.|CHU Clermont-Ferrand, Service de Cytogénétique Médicale, 63003 Clermont-Ferrand, France.
authors.forename: Andreï
authors.initials: A
authors.lastname: Tchirkov
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy / Q000628:therapy*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D045744:Cell Line, Tumor; D004273:DNA, Neoplasm / Q000187:drug effects*; D054856:G-Quadruplexes / Q000187:drug effects*; D005909:Glioblastoma / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy / Q000628:therapy*; D064593:Heterografts; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy / Q000628:therapy*; D051379:Mice; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage*; D019098:Telomerase / Q000235:genetics; D035321:Telomeric Repeat Binding Protein 1 / Q000235:genetics
chemical_list: D004273:DNA, Neoplasm; D011838:Radiation-Sensitizing Agents; D035321:Telomeric Repeat Binding Protein 1; C509186:TERT protein, human; D019098:Telomerase