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

doi:10.1038/srep16255

Journal articles

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.

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Life Sciences [q-bio] / Genetics

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

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