Telomeres and telomerase: Pharmacological targets for new anticancer strategies?
Telomeres are located at the ends of eukaryotic chromosomes. Human telomerase, a cellular reverse transcriptase, is a ribonucleoprotein enzyme that catalyzes the synthesis and extension of telomeric DNA. It is composed of at least, a template RNA component (hTR; human Telomerase RNA) and a catalytic subunit, the telomerase reverse transcriptase (hTERT). The absence of telomerase is associated with telomere shortening and aging of somatic cells, while high telomerase activity is observed in over 85% of human cancer cells, strongly indicating its key role during tumorigenesis. Several details regarding telomere structure and telomerase regulation have already been elucidated, providing new targets for therapeutic exploitation. Further support for anti-telomerase approaches comes from recent studies indicating that telomerase is endowed of additional functions in the control of growth and survival of tumor cells that do not depend only on the ability of this enzyme to maintain telomere length. This observation suggests that inhibiting telomerase or its synthesis may have additional anti-proliferative and apoptosis inducing effect, independently of the reduction of telomere length during cell divisions. This article reviews the basic information about the biology of telomeres and telomerase and attempts to present various approaches that are currently under investigation to inhibit its expression and its activity. We summarize herein distinct anti-telomerase approaches like antisense strategies, reverse transcriptase inhibitors, and G-quadruplex interacting agents, and also review molecules targeting hTERT expression, such as retinoids and evaluate them for their therapeutic potential. "They conceive a certain theory, and everything has to fit into that theory. If one little fact will not fit it, they throw it aside. But it is always the facts that will not fit in that are significant". "Death on the Nile". Agatha Christie.
Pendino
F
F
INSERM U685, Hôpital Saint-Louis, Institut d'Hématologie, 1, avenue Claude Vellefaux, 75010 Paris, France.
Tarkanyi
I
I
Dudognon
C
C
Hillion
J
J
Lanotte
M
M
Aradi
J
J
Ségal-Bendirdjian
E
E
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019098:Telomerase / Q000037:antagonists & inhibitors*; D016615:Telomere / Q000737:chemistry / Q000187:drug effects*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D019098:Telomerase