Abstract
New anti-telomere strategies represent important goals for the development of selective cancer therapies. In this study, we reported that uncapped telomeres, resulting from pharmacological stabilization of quadruplex DNA by RHPS4 (3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate), trigger specific recruitment and activation of poly-adenosine diphosphate (ADP) ribose polymerase I (PARP1) at the telomeres, forming several ADP-ribose polymers that co-localize with the telomeric repeat binding factor 1 protein and are inhibited by selective PARP(s) inhibitors or PARP1-specific small interfering RNAs. The knockdown of PARP1 prevents repairing of RHPS4-induced telomere DNA breaks, leading to increases in chromosome abnormalities and eventually to the inhibition of tumor cell growth both in vitro and in xenografts. More interestingly, the integration of a TOPO1 inhibitor on the combination treatment proved to have a high therapeutic efficacy ensuing a complete regression of the tumor as well as a significant increase in overall survival and cure of mice even when treatments started at a very late stage of tumor growth. Overall, this work reveals the unexplored link between the PARP1 and G-quadruplex ligands and demonstrates the excellent efficacy of a multi-component strategy based on the use of PARP inhibitors in telomere-based therapy.
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Acknowledgements
This work was supported by grants from the Italian Association for Cancer Research (AIRC), Ministero della Salute and Ligue Nationale contre le Cancer (EG ‘équipe labellisée’). ES and MP are recipients of fellowships from the Italian Foundation for Cancer Research (FIRC). We thank Mrs Carmen D’Angelo for generating HT29 cells that express the luciferase gene and Mrs Adele Petricca for her helpful assistance in typing the manuscript. We are also grateful to Tania Merlino for the English revision.
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Salvati, E., Scarsella, M., Porru, M. et al. PARP1 is activated at telomeres upon G4 stabilization: possible target for telomere-based therapy. Oncogene 29, 6280–6293 (2010). https://doi.org/10.1038/onc.2010.344
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DOI: https://doi.org/10.1038/onc.2010.344
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