Highly efficient radiosensitization of human glioblastoma and lung cancer cells by a G-quadruplex DNA binding compound

Patrick Merle; Marine Gueugneau; Marie-Paule Teulade-Fichou; Mélanie Müller-Barthélémy; Simon Amiard; Emmanuel Chautard; Corinne Guetta; Véronique Dedieu; Yves Communal; Jean-Louis Mergny; Maria Gallego; Charles White; Pierre Verrelle; Andrei Tchirkov

Highly efficient radiosensitization of human glioblastoma and lung cancer cells by a G-quadruplex DNA binding compound

Patrick Merle ^{1, 2} Marine Gueugneau ¹ Marie-Paule Teulade-Fichou ³ Mélanie Müller-Barthélémy ^{1, 4} Simon Amiard ⁵ Emmanuel Chautard ^{1, 4} Corinne Guetta ⁶ Véronique Dedieu ^{1, 4} Yves Communal ⁷ Jean-Louis Mergny ⁸ Maria Gallego ⁵ Charles White ⁵ Pierre Verrelle ^{9, 1} Andrei Tchirkov ^{9, 1}

1 CREaT - Cancer Resistance Exploring and Targeting

2 Service de Pneumologie Oncologie Thoracique [CHU Clermont-Ferrand]

3 Institut Curie

4 Département de Radiothérapie [Centre Jean Perrin, Clermont-Ferrand]

5 GReD - Génétique, Reproduction et Développement - Clermont Auvergne

6 Chimie, Modélisation et Imagerie pour la Biologie [Orsay]

7 laboratoire OncoGènAuvergne [Centre Jean Perrin, Clermont-Ferrand]

8 Régulation et dynamique des génomes

9 Centre Jean Perrin

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.

Document type :

Journal articles

Domain :

Life Sciences [q-bio] / Genetics

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https://www.hal.inserm.fr/inserm-01907350
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Submitted on : Monday, October 29, 2018 - 9:28:29 AM
Last modification on : Friday, November 8, 2019 - 10:52:30 AM

Highly efficient radiosensitization of human glioblastoma and lung cancer cells by a G-quadruplex DNA binding compound

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Highly efficient radiosensitization of human glioblastoma and lung cancer cells by a G-quadruplex DNA binding compound

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