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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Patrick Merle, Marine Gueugneau, Marie-Paule Teulade-Fichou, Mélanie Müller-Barthélémy, Simon Amiard, et al.. Highly efficient radiosensitization of human glioblastoma and lung cancer cells by a G-quadruplex DNA binding compound. Scientific Reports, Nature Publishing Group, 2015, 5 (1), ⟨10.1038/srep16255⟩. ⟨inserm-01907350⟩

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