Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET

User menu

  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
Molecular Pharmacology
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET
  • My alerts
  • Log in
  • My Cart
Molecular Pharmacology

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Visit molpharm on Facebook
  • Follow molpharm on Twitter
  • Follow molpharm on LinkedIn
Research ArticleArticle

A New Steroid Derivative Stabilizes G-Quadruplexes and Induces Telomere Uncapping in Human Tumor Cells

Bertrand Brassart, Dennis Gomez, Anne De Cian, Rajaa Paterski, Alain Montagnac, Khuong-Huu Qui, Nassima Temime-Smaali, Chantal Trentesaux, Jean-Louis Mergny, Françoise Gueritte and Jean-François Riou
Molecular Pharmacology September 2007, 72 (3) 631-640; DOI: https://doi.org/10.1124/mol.107.036574
Bertrand Brassart
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Dennis Gomez
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Anne De Cian
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Rajaa Paterski
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Alain Montagnac
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Khuong-Huu Qui
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nassima Temime-Smaali
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Chantal Trentesaux
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jean-Louis Mergny
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Françoise Gueritte
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jean-François Riou
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF
Loading

Abstract

Human telomeric DNA consists of tandem repeats of the sequence d(TTAGGG) with a 3′ single-stranded extension (the G-overhang). The stabilization of G-quadruplexes in the human telomeric sequence by small-molecule ligands inhibits the activity of telomerase and results in telomere uncapping, leading to senescence or apoptosis of tumor cells. Therefore, the search for new and selective G-quadruplex ligands is of considerable interest because a selective ligand might provide a telomere-targeted therapeutic approach to treatment of cancer. We have screened a bank of derivatives from natural and synthetic origin using a temperature fluorescence assay and have identified two related compounds that induce G-quadruplex stabilization: malouetine and steroid FG. These steroid derivatives have nonplanar and nonaromatic structures, different from currently known G-quadruplex ligands. Malouetine is a natural product isolated from the leaves of Malouetia bequaaertiana E. Woodson and is known for its curarizing and DNA-binding properties. Steroid FG, a funtumine derivative substituted with a guanylhydrazone moiety, interacted selectively with the telomeric G-quadruplex in vitro. This derivative induced senescence and telomere shortening of HT1080 tumor cells at submicromolar concentrations, corresponding to the phenotypic inactivation of telomerase activity. In addition, steroid FG induced a rapid degradation of the telomeric G-overhang and the formation of anaphase bridges, characteristics of telomere uncapping. Finally, the expression of protection of telomere 1 (POT1) induced resistance to the growth effect of steroid FG. These results indicate that these steroid ligands represent a new class of telomere-targeted agents with potential as antitumor drugs.

Footnotes

  • This work was supported by grants from the “Ligue Nationale Contre le Cancer, Equipe labelisée 2006” (to J.F.R.), by the Association pour la Recherche contre le Cancer 3365 (to J.L.M.), and from the European Union FP6 “MolCancerMed” program (LSHC-CT-2004-502943 to J.L.M.). D.G. and B.B. have been supported by a postdoctoral fellowship from the Institut de Chimie des Substances Naturelles/Centre National de la Recherche Scientifique. N.T.-S. is supported by a doctoral fellowship from the “Région Champagne Ardenne”.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

  • doi:10.1124/mol.107.036574.

  • ABBREVIATIONS: hTERT, human telomerase reverse transcriptase; PCR, polymerase chain reaction; POT1, protection of telomere 1; TBE, Tris-borate-EDTA; DAPI, 4,6-diamidino-2-phenylindole; TRF, terminal restriction fragment; steroid FG, a funtumine derivative substituted witha guanylhydrazone moiety; EtBr, ethidium bromide; TRF, telomere repeat factor.

  • ↵1 Current affiliation: Institut de Pharmacologie et de Biologie Structurale, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5089, Toulouse, France.

  • ↵2 Current affiliation: Laboratoire de Physiologie Cellulaire Végétale, Institut de Recherches en Technologie et Sciences pour le Vivant, Commissariat à l'Energie Atomique Grenoble, Grenoble, France.

    • Received March 29, 2007.
    • Accepted June 20, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
View Full Text

MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years. 

Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page. 

 

  • Click here for information on institutional subscriptions.
  • Click here for information on individual ASPET membership.

 

Log in using your username and password

Forgot your user name or password?

Purchase access

You may purchase access to this article. This will require you to create an account if you don't already have one.
PreviousNext
Back to top

In this issue

Molecular Pharmacology: 72 (3)
Molecular Pharmacology
Vol. 72, Issue 3
1 Sep 2007
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Back Matter (PDF)
  • Editorial Board (PDF)
  • Front Matter (PDF)
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Molecular Pharmacology article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
A New Steroid Derivative Stabilizes G-Quadruplexes and Induces Telomere Uncapping in Human Tumor Cells
(Your Name) has forwarded a page to you from Molecular Pharmacology
(Your Name) thought you would be interested in this article in Molecular Pharmacology.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleArticle

A New Steroid Derivative Stabilizes G-Quadruplexes and Induces Telomere Uncapping in Human Tumor Cells

Bertrand Brassart, Dennis Gomez, Anne De Cian, Rajaa Paterski, Alain Montagnac, Khuong-Huu Qui, Nassima Temime-Smaali, Chantal Trentesaux, Jean-Louis Mergny, Françoise Gueritte and Jean-François Riou
Molecular Pharmacology September 1, 2007, 72 (3) 631-640; DOI: https://doi.org/10.1124/mol.107.036574

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Research ArticleArticle

A New Steroid Derivative Stabilizes G-Quadruplexes and Induces Telomere Uncapping in Human Tumor Cells

Bertrand Brassart, Dennis Gomez, Anne De Cian, Rajaa Paterski, Alain Montagnac, Khuong-Huu Qui, Nassima Temime-Smaali, Chantal Trentesaux, Jean-Louis Mergny, Françoise Gueritte and Jean-François Riou
Molecular Pharmacology September 1, 2007, 72 (3) 631-640; DOI: https://doi.org/10.1124/mol.107.036574
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Materials and Methods
    • Results
    • Discussion
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • P2X7 Positive Modulator Structure-Activity Relationship
  • Predicting Drug Interactions with ENT1 and ENT2
  • GABAAR Molecular Identity in Oligodendrocytes
Show more Articles

Similar Articles

  • Home
  • Alerts
Facebook   Twitter   LinkedIn   RSS

Navigate

  • Current Issue
  • Fast Forward by date
  • Fast Forward by section
  • Latest Articles
  • Archive
  • Search for Articles
  • Feedback
  • ASPET

More Information

  • About Molecular Pharmacology
  • Editorial Board
  • Instructions to Authors
  • Submit a Manuscript
  • Customized Alerts
  • RSS Feeds
  • Subscriptions
  • Permissions
  • Terms & Conditions of Use

ASPET's Other Journals

  • Drug Metabolism and Disposition
  • Journal of Pharmacology and Experimental Therapeutics
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-0111 (Online)

Copyright © 2021 by the American Society for Pharmacology and Experimental Therapeutics