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Apoptosis related to telomere instability and cell cycle alterations in human glioma cells treated by new highly selective G-quadruplex ligands

Oncogene volume 24, pages 2917–2928 (2005)Cite this article

Abstract

Telomerase represents a relevant target for cancer therapy. Molecules able to stabilize the G-quadruplex (G4), a structure adopted by the 3′-overhang of telomeres, are thought to inhibit telomerase by blocking its access to telomeres. We investigated the cellular effects of four new 2,6-pyridine-dicarboxamide derivatives displaying strong selectivity for G4 structures and strong inhibition of telomerase in in vitro assays. These compounds inhibited cell proliferation at very low concentrations and then induced a massive apoptosis within a few days in a dose-dependent manner in cultures of three telomerase-positive glioma cell lines, T98G, CB193 and U118-MG. They had also antiproliferative effects in SAOS-2, a cell line in which telomere maintenance involves an alternative lengthening of telomeres (ALT) mechanism. We show that apoptosis was preceded by multiple alterations of the cell cycle: activation of S-phase checkpoints, dramatic increase of metaphase duration and cytokinesis defects. These effects were not associated with telomere shortening, but they were directly related to telomere instability involving telomere end fusion and anaphase bridge formation. Pyridine-based G-quadruplex ligands are therefore promising agents for the treatment of various tumors including malignant gliomas.

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Acknowledgements

We thank A Boistard, E Goodall, O Etienne, E Nowak, P Millet, C Silva Lages (CEA, Fontenay-aux-Roses, France), L Guittat and L Lacroix (MNHN, Paris, France) for technical support and helpful discussions. This work was support by an Action Concertée Incitative ‘Molécules et Cibles Thérapeutiques’ grant from the French Ministry of Research and an Association pour la recherche sur le Cancer grant (grant 3365 to J-L M and grant 4691 to J-F R).

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Authors and Affiliations

  1. Laboratoire de Radiopathologie, DSV/DRR, CEA, 18 route du Panorama, 92265, Fontenay-aux-Roses, France

    Gaëlle Pennarun, Christine Granotier, Laurent R Gauthier, Françoise Hoffschir & François D Boussin

  2. Laboratoire d'Onco-Pharmacologie, JE 2428, Université de Reims Champagne-Ardenne, 51096, Reims, France

    Dennis Gomez & Jean-François Riou

  3. Aventis Pharma SA, Centre de Recherche de Paris, 94403, Vitry-sur-Seine, France

    Eliane Mandine & Patrick Mailliet

  4. Laboratoire de Biophysique, INSERM U565, CNRS UMR 5153, Muséum National d'Histoire Naturelle USM 503, 75005, Paris, France

    Jean-Louis Mergny

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  1. Gaëlle Pennarun
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  2. Christine Granotier
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Correspondence to François D Boussin.

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Pennarun, G., Granotier, C., Gauthier, L. et al. Apoptosis related to telomere instability and cell cycle alterations in human glioma cells treated by new highly selective G-quadruplex ligands. Oncogene 24, 2917–2928 (2005). https://doi.org/10.1038/sj.onc.1208468

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