Cell senescence and telomere shortening induced by a new series of specific G-quadruplex DNA ligands

Riou, Jean‐François; Guittat, Lionel; Mailliet, Patrick; Laoui, Abdelazize; Renou, E.; Petitgenet, Odile; Mégnin-Chanet, Frédérique; Hélène, Claude; Mergny, Jean‐Louis

doi:10.1073/pnas.052698099

Cited by 395 publications

(342 citation statements)

References 48 publications

(55 reference statements)

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“…The most potent G4 stabiliser (meridine) is also the most potent telomerase inhibitor. This is in agreement with what was previously observed with dibenzophenanthro-lines [36] or triazines [65]. This should stimulate the interest in the modification of these marine alkaloids in order to provide ligands with higher affinity and inhibitory potential.…”

Section: Discussionsupporting

confidence: 92%

Ascididemin and meridine stabilise G-quadruplexes and inhibit telomerase in vitro

Guittat

Cian

Rosu

et al. 2005

Biochimica et Biophysica Acta (BBA) - General Subjects

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Ascididemin and Meridine are two marine compounds with pyridoacridine skeletons known to exhibit interesting antitumour activities. These molecules have been reported to behave like DNA intercalators. In this study, dialysis competition assay and mass spectrometry experiments were used to determine the affinity of ascididemin and meridine for DNA structures among duplexes, triplexes, quadruplexes and single-strands. Our data confirm that ascididemin and meridine interact with DNA but also recognize triplex and quadruplex structures. These molecules exhibit a significant preference for quadruplexes over duplexes or single-strands. Meridine is a stronger quadruplex ligand and therefore a stronger telomerase inhibitor than ascididemin (IC 50 =ll and >80 µM, respectively in a standard TRAP assay).

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Section: Discussionsupporting

confidence: 92%

Ascididemin and meridine stabilise G-quadruplexes and inhibit telomerase in vitro

Guittat

Cian

Rosu

et al. 2005

Biochimica et Biophysica Acta (BBA) - General Subjects

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“…Cryptolepine stabilizes the F21MB quadruplex by 3 °C at 3 µM, whereas the best G4 ligands stabilize by 20 °C or more at 1 µM compound [44]. It is not a potent telomerase inhibitor (IC 50 = 9.4 µM); the best inhibitors described so far have an IC 50 of 50 nM or lower [37,44,[48][49][50].…”

Section: Discussionmentioning

confidence: 99%

Interactions of cryptolepine and neocryptolepine with unusual DNA structures

et al. 2003

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1 These authors contributed equally to this work. AbstractCryptolepine, the main alkaloid present in the roots of Cryptolepis sanguinolenta, presents a large spectrum of biological properties. It has been reported to behave like a DNA intercalator with a preference for GC-rich sequences. In this study, dialysis competition assay and mass spectrometry experiments were used to determine the affinity of cryptolepine and neocryptolepine for DNA structures among duplexes, triplexes, quadruplexes and single strands. Our data confirm that cryptolepine and neocryptolepine prefer GC over AT-rich duplex sequences, but also recognize triplex and quadruplex structures. These compounds are weak telomerase inhibitors and exhibit a significant preference for triplexes over quadruplexes or duplexes.

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“…Agents that stabilize G-quadruplexes have the potential to interfere with telomere replication by blocking the elongation step catalysed by telomerase, and thus are very attractive targets for drug design (Mergny and Helene, 1998). Small molecular ligands that selectively stabilize the telomeric G-quadruplex induce telomere shortening and replicative senescence (Han and Hurley, 2000;Gowan et al, 2001Gowan et al, , 2002Riou et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

G-Quadruplex stabilization by telomestatin induces TRF2 protein dissociation from telomeres and anaphase bridge formation accompanied by loss of the 3′ telomeric overhang in cancer cells

et al. 2006

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Inhibition of telomerase activity by telomerase inhibitors induces a gradual loss of telomeres, and this in turn causes cancer cells to enter to a crisis stage. Here, we report the telomerase inhibitor telomestatin, which is known to stabilize G-quadruplex structures at 3 0 single-stranded telomeric overhangs (G-tails), rapidly dissociates TRF2 from telomeres in cancer cells within a week, when given at a concentration that does not cause normal cells to die. The G-tails were dramatically reduced upon short-term treatment with the drug in cancer cell lines, but not in normal fibroblasts and epithelial cells. In addition, telomestatin also induced anaphase bridge formation in cancer cell lines. These effects of telomestatin were similar to those of dominant negative TRF2, which also causes a prompt loss of the telomeric G-tails and induces an anaphase bridge. These results indicate that telomestatin exerts its anticancer effect not only through inhibiting telomere elongation, but also by rapidly disrupting the capping function at the very ends of telomeres. Unlike conventional telomerase inhibitors that require long-term treatments, the G-quadruplex stabilizer telomestatin induced prompt cell death, and it was selectively effective in cancer cells. This study also identifies the TRF2 protein as a therapeutic target for treating many types of cancer which have the TRF2 protein at caps of the telomere DNA of each chromosome.

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Cell senescence and telomere shortening induced by a new series of specific G-quadruplex DNA ligands

Cited by 395 publications

References 48 publications

Ascididemin and meridine stabilise G-quadruplexes and inhibit telomerase in vitro

Ascididemin and meridine stabilise G-quadruplexes and inhibit telomerase in vitro

Interactions of cryptolepine and neocryptolepine with unusual DNA structures

G-Quadruplex stabilization by telomestatin induces TRF2 protein dissociation from telomeres and anaphase bridge formation accompanied by loss of the 3′ telomeric overhang in cancer cells

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