期刊
ONCOGENE
卷 29, 期 47, 页码 6280-6293出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2010.344
关键词
PARP1; G4 ligand; combination therapy
资金
- Italian Association for Cancer Research (AIRC)
- Ministero della Salute
- Ligue Nationale contre le Cancer (EG equipe labellisee)
- Italian Foundation for Cancer Research (FIRC)
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. Oncogene (2010) 29, 6280-6293; doi:10.1038/onc.2010.344; published online 30 August 2010
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