Inhibition of Human Telomerase by a G-Quadruplex-Interactive Compound

Sun, Daekyu; Thompson, B.; Cathers, Brian E.; Salazar, Miguel; Kerwin, Sean M.; Trent, John O.; Jenkins, Terence C.; Neidle, Stephen; Hurley, Laurence H.

doi:10.1021/jm970199z

Cited by 771 publications

(604 citation statements)

References 25 publications

(33 reference statements)

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“…The number of G4 ligands has grown rapidly over a few years: a range of molecules has been shown to inhibit telomerase through binding to its substrate [14,26,27,36,[44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59]. On the other hand, few natural products have been reported as G-quadruplex-mediated telomerase inhibitors, although one, telomestatin, is exceptionally potent with an IC50 of 5 nM against telomerase [25].…”

Section: Discussionmentioning

confidence: 99%

“…This structure has been shown to directly inhibit telomerase elongation in vitro [13]. Therefore, ligands that selectively bind to G-quadruplex structures may interfere with telomere structure and telomere elongation and replication of cancer cells [14,15]. Several reviews concerning telomerase inhibitors in general or quadruplex-based telomerase inhibitors have been published in the last few years [16][17][18][19][20][21][22][23].…”

Section: (B) a G-quartet (Left) And A Schematic Drawing Of An Intramentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

Section: (B) a G-quartet (Left) And A Schematic Drawing Of An Intramentioning

confidence: 99%

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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“…The non-folded, single-stranded form of the primer is required for optimal telomerase activity and qua-druplex formation has been shown to directly inhibit telomerase elongation in vitro [20]. A growing number of small molecules have been discovered to inhibit telomerase activ ity by inducing and/or stabilizing G-quartet structure [45,46], including l0H-indolo [3,2-b] quinoline derivatives [47]. Therefore, here, we performed a TRAP assay with increasing concentrations (ranging from 1 to 50 µM) of the compound.…”

Section: Telomerase Inhibitionmentioning

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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“…A property of G-rich, single-stranded structure assembled around a core stack of guanines arranged in almost-planar, hydrogen-bonded tetrads. Ionic conditions that favor quadruplex formation have been shown to inhibit telomerase (Zahler et al, 1991), while small molecules that stabilize or promote the formation of quadruplex also show inhibitory activity (Sun et al, 1997;Wheelhouse et al, 1998;Izbicka et al, 1999;Perry and Jenkins, 1999). Thus, quadruplex DNA presents a target of considerable importance in DNA-directed drug design.…”

Section: Introductionmentioning

confidence: 99%

Activity of a novel G-quadruplex-interactive telomerase inhibitor, telomestatin (SOT-095), against human leukemia cells: involvement of ATM-dependent DNA damage response pathways

et al. 2003

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The telomerase complex is responsible for telomere maintenance and represents a promising neoplasia therapeutic target. In order to determine whether G-quadruplex-interactive telomerase inhibitor, telomestatin (SOT-095), might have effects on telomere dynamics and to evaluate the clinical utility, we assessed the effects of telomestatin on BCR-ABL-positive human leukemia cells. We found that treatment with telomestatin reproducibly inhibited telomerase activity in the BCR-ABLpositive leukemic cell lines OM9;22 and K562, resulting in telomere shortening. Inhibition of telomerase activity by telomestatin disrupts telomere maintenance and ultimately results in telomere dysfunction. Telomestatin completely suppressed the plating efficiency of K562 cells at 1 lm; however, telomestatin had less effects on BFU-Es and CFU-GMs colony formation from normal bone marrow CD34-positive cells. Enhanced chemosensitivity toward imatinib and chemotherapeutic agents was also observed in telomestatin-treated K562 cells. Further, the combination of telomestatin plus imatinib more effectively inhibited hematopoietic colony formation by primary human chronic myelogenous leukemia cells. Last, telomestatin induced the activation of ATM and Chk2, and subsequently increased the expression of p21 CIP1 and p27 KIP1 . These results demonstrate that telomere dysfunction induced by telomestatin activates the ATM-dependent DNA damage response. We conclude that telomerase inhibitors combined with the use of imatinib and other chemotherapeutic agents may be very useful for the treatment of human leukemia.

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Inhibition of Human Telomerase by a G-Quadruplex-Interactive Compound

Cited by 771 publications

References 25 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

Activity of a novel G-quadruplex-interactive telomerase inhibitor, telomestatin (SOT-095), against human leukemia cells: involvement of ATM-dependent DNA damage response pathways

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