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Targeting human telomerase for cancer therapeutics

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Abstract

The enzyme telomerase is involved in the replication of telomeres, specialized structures that cap and protect the ends of chromosomes. Its activity is required for maintenance of telomeres and for unlimited lifespan, a hallmark of cancer cells. Telomerase is overexpressed in the vast majority of human cancer cells and therefore represents an attractive target for therapy. Several approaches have been developed to inhibit this enzyme through the targeting of its RNA or catalytic components as well as its DNA substrate, the single-stranded 3′-telomeric overhang. Telomerase inhibitors are chemically diverse and include modified oligonucleotides as well as small diffusable molecules, both natural and synthetic. This review presents an update of recent investigations pertaining to these agents and discusses their biological properties in the context of the initial paradigm that the exposure of cancer cells to these agents should lead to progressive telomere shortening followed by a delayed growth arrest response.

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Abbreviations

2′MOE:

2′-O-(2-methoxyethyl) RNA

2′OMe:

2′-O-methyl-RNA

hTERT:

human Telomerase Reverse Transcriptase

hTR:

human Telomerase RNA

LNA:

locked nucleic acids

PN:

phosphoramidate

PNA:

peptide nucleic acids

PS:

phosphorothioate

TRAP:

Telomeric Repeat Amplification Protocol

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Authors and Affiliations

  1. Laboratoire de Biophysique, Muséum National d’Histoire Naturelle USM503, INSERM U 565, CNRS UMR 5153, 43, rue Cuvier, 75231, Paris cedex 05, France

    Lionel Guittat, Patrizia Alberti, Anne De Cian, Gaëlle Pennarun, Laurent Lacroix & Jean-Louis Mergny

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

    Dennis Gomez, Thibault Lemarteleur, Rajaa Paterski, Hamid Morjani, Chantal Trentesaux & Jean-François Riou

  3. Laboratoire de Radiopathologie, CEA, 92265, Fontenay aux Roses, France

    Gaëlle Pennarun & François Boussin

  4. Aventis Pharma SA, Centre de Recherche de Paris, Quai Jules Guesde, 94403, Vitry sur Seine, France

    Chafke Belmokhtar, Eliane Mandine & Patrick Mailliet

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  1. Lionel Guittat
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Guittat, L., Alberti, P., Gomez, D. et al. Targeting human telomerase for cancer therapeutics. Cytotechnology 45, 75–90 (2004). https://doi.org/10.1007/s10616-004-5127-z

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