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

DNA-Dependent Protein Kinase and Ataxia Telangiectasia Mutated (ATM) Promote Cell Survival in Response to NK314, a Topoisomerase IIα Inhibitor

Lei Guo, Xiaojun Liu, Yingjun Jiang, Kiyohiro Nishikawa and William Plunkett
Molecular Pharmacology August 2011, 80 (2) 321-327; DOI: https://doi.org/10.1124/mol.109.057125
Lei Guo
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Xiaojun Liu
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yingjun Jiang
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kiyohiro Nishikawa
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
William Plunkett
  • 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 + SI
  • PDF
Loading

Abstract

4-Hydroxy-5-methoxy-2,3-dihydro-1H-[1,3]benzodioxolo[5,6-c]pyrrolo[1,2-f]-phenanthridium chloride (NK314) is a benzo[c] phenanthridine alkaloid that inhibits topoisomerase IIα, leading to the generation of DNA double-strand breaks (DSBs) and activating the G2 checkpoint pathway. The purpose of the present studies was to investigate the DNA intercalating properties of NK314, to evaluate the DNA repair mechanisms activated in cells that may lead to resistance to NK314, and to develop mechanism-based combination strategies to maximize the antitumor effect of the compound. A DNA unwinding assay indicated that NK314 intercalates in DNA, a property that likely cooperates with its ability to trap topoisomerase IIα in its cleavage complex form. The consequence of this is the formation of DNA DSBs, as demonstrated by pulsed-field gel electrophoresis and H2AX phosphorylation. Clonogenic assays demonstrated a significant sensitization in NK314-treated cells deficient in DNA-dependent protein kinase (DNA-PK) catalytic subunit, Ku80, ataxia telangiectasia mutated (ATM), BRCA2, or XRCC3 compared with wild-type cells, indicating that both nonhomologous end-joining and homologous recombination DNA repair pathways contribute to cell survival. Furthermore, both the DNA-PK inhibitor 8-(4-dibenzothienyl)-2-(4-morpholinyl)-4H-1-benzopyran-4-one (NU7441) and the ATM inhibitor 2-(4-morpholinyl)-6-(1-thianthrenyl)-4H-pyran-4-one (KU55933) significantly sensitized cells to NK314. We conclude that DNA-PK and ATM contribute to cell survival in response to NK314 and could be potential targets for abrogating resistance and maximizing the antitumor effect of NK314.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This work was supported by the National Institutes of Health National Cancer Institute, Department of Health and Human Services [Grants CA28596, CA100632, CA16672].

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

    doi:10.1124/mol.109.057125.

  • ABBREVIATIONS:

    DSB
    DNA double-strand break
    ATM
    ataxia telangiectasia mutated
    ATR
    ataxia telangiectasia mutated and rad3-related
    DNA-PK
    DNA-dependent protein kinase
    DNA-PKcs
    DNA-dependent protein kinase catalytic subunit
    FBS
    fetal bovine serum
    HR
    homologous recombination
    NHEJ
    nonhomologous end-joining
    PFGE
    pulsed-field gel electrophoresis
    NU7441
    8-(4-dibenzothienyl)-2-(4-morpholinyl)-4H-1-benzopyran-4-one
    KU55933
    2-(4-morpholinyl)-6-(1-thianthrenyl)-4H-pyran-4-one
    MEM
    minimum essential medium
    PBS
    phosphate-buffered saline
    m-AMSA
    4′-(9-acridinylamino)methanesulfon-m-anisidide.

  • Received April 30, 2009.
  • Accepted May 5, 2011.
  • Copyright © 2011 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: 80 (2)
Molecular Pharmacology
Vol. 80, Issue 2
1 Aug 2011
  • 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.
DNA-Dependent Protein Kinase and Ataxia Telangiectasia Mutated (ATM) Promote Cell Survival in Response to NK314, a Topoisomerase IIα Inhibitor
(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

DNA-Dependent Protein Kinase and Ataxia Telangiectasia Mutated (ATM) Promote Cell Survival in Response to NK314, a Topoisomerase IIα Inhibitor

Lei Guo, Xiaojun Liu, Yingjun Jiang, Kiyohiro Nishikawa and William Plunkett
Molecular Pharmacology August 1, 2011, 80 (2) 321-327; DOI: https://doi.org/10.1124/mol.109.057125

Citation Manager Formats

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

DNA-Dependent Protein Kinase and Ataxia Telangiectasia Mutated (ATM) Promote Cell Survival in Response to NK314, a Topoisomerase IIα Inhibitor

Lei Guo, Xiaojun Liu, Yingjun Jiang, Kiyohiro Nishikawa and William Plunkett
Molecular Pharmacology August 1, 2011, 80 (2) 321-327; DOI: https://doi.org/10.1124/mol.109.057125
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
    • Introduction
    • Materials and Methods
    • Results
    • Discussion
    • Authorship Contributions
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • 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