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
Journal of Pharmacology and Experimental Therapeutics
  • 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
Journal of Pharmacology and Experimental Therapeutics

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 jpet on Facebook
  • Follow jpet on Twitter
  • Follow jpet on LinkedIn
Research ArticleChemotherapy, Antibiotics, and Gene Therapy

Rationale for Poly(ADP-ribose) Polymerase (PARP) Inhibitors in Combination Therapy with Camptothecins or Temozolomide Based on PARP Trapping versus Catalytic Inhibition

Junko Murai, Yiping Zhang, Joel Morris, Jiuping Ji, Shunichi Takeda, James H. Doroshow and Yves Pommier
Journal of Pharmacology and Experimental Therapeutics June 2014, 349 (3) 408-416; DOI: https://doi.org/10.1124/jpet.113.210146
Junko Murai
Developmental Therapeutics Branch, Laboratory of Molecular Pharmacology, Center for Cancer Research (Ju.M., J.H.D., Y.P.), National Clinical Target Validation Laboratory (Y.Z., J.J.), and Division of Cancer Treatment and Diagnosis (Jo.M., J.H.D.), National Cancer Institute, National Institutes of Health, Bethesda, Maryland; and Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, Yoshidakonoe, Sakyo-ku, Kyoto, Japan (Ju.M., S.T.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yiping Zhang
Developmental Therapeutics Branch, Laboratory of Molecular Pharmacology, Center for Cancer Research (Ju.M., J.H.D., Y.P.), National Clinical Target Validation Laboratory (Y.Z., J.J.), and Division of Cancer Treatment and Diagnosis (Jo.M., J.H.D.), National Cancer Institute, National Institutes of Health, Bethesda, Maryland; and Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, Yoshidakonoe, Sakyo-ku, Kyoto, Japan (Ju.M., S.T.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Joel Morris
Developmental Therapeutics Branch, Laboratory of Molecular Pharmacology, Center for Cancer Research (Ju.M., J.H.D., Y.P.), National Clinical Target Validation Laboratory (Y.Z., J.J.), and Division of Cancer Treatment and Diagnosis (Jo.M., J.H.D.), National Cancer Institute, National Institutes of Health, Bethesda, Maryland; and Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, Yoshidakonoe, Sakyo-ku, Kyoto, Japan (Ju.M., S.T.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jiuping Ji
Developmental Therapeutics Branch, Laboratory of Molecular Pharmacology, Center for Cancer Research (Ju.M., J.H.D., Y.P.), National Clinical Target Validation Laboratory (Y.Z., J.J.), and Division of Cancer Treatment and Diagnosis (Jo.M., J.H.D.), National Cancer Institute, National Institutes of Health, Bethesda, Maryland; and Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, Yoshidakonoe, Sakyo-ku, Kyoto, Japan (Ju.M., S.T.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Shunichi Takeda
Developmental Therapeutics Branch, Laboratory of Molecular Pharmacology, Center for Cancer Research (Ju.M., J.H.D., Y.P.), National Clinical Target Validation Laboratory (Y.Z., J.J.), and Division of Cancer Treatment and Diagnosis (Jo.M., J.H.D.), National Cancer Institute, National Institutes of Health, Bethesda, Maryland; and Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, Yoshidakonoe, Sakyo-ku, Kyoto, Japan (Ju.M., S.T.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
James H. Doroshow
Developmental Therapeutics Branch, Laboratory of Molecular Pharmacology, Center for Cancer Research (Ju.M., J.H.D., Y.P.), National Clinical Target Validation Laboratory (Y.Z., J.J.), and Division of Cancer Treatment and Diagnosis (Jo.M., J.H.D.), National Cancer Institute, National Institutes of Health, Bethesda, Maryland; and Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, Yoshidakonoe, Sakyo-ku, Kyoto, Japan (Ju.M., S.T.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yves Pommier
Developmental Therapeutics Branch, Laboratory of Molecular Pharmacology, Center for Cancer Research (Ju.M., J.H.D., Y.P.), National Clinical Target Validation Laboratory (Y.Z., J.J.), and Division of Cancer Treatment and Diagnosis (Jo.M., J.H.D.), National Cancer Institute, National Institutes of Health, Bethesda, Maryland; and Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, Yoshidakonoe, Sakyo-ku, Kyoto, Japan (Ju.M., S.T.)
  • 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

We recently showed that poly(ADP-ribose) polymerase (PARP) inhibitors exert their cytotoxicity primarily by trapping PARP-DNA complexes in addition to their NAD+-competitive catalytic inhibitory mechanism. PARP trapping is drug-specific, with olaparib exhibiting a greater ability than veliparib, whereas both compounds are potent catalytic PARP inhibitors. Here, we evaluated the combination of olaparib or veliparib with therapeutically relevant DNA-targeted drugs, including the topoisomerase I inhibitor camptothecin, the alkylating agent temozolomide, the cross-linking agent cisplatin, and the topoisomerase II inhibitor etoposide at the cellular and molecular levels. We determined PARP-DNA trapping and catalytic PARP inhibition in genetically modified chicken lymphoma DT40, human prostate DU145, and glioblastoma SF295 cancer cells. For camptothecin, both PARP inhibitors showed highly synergistic effects due to catalytic PARP inhibition, indicating the value of combining either veliparib or olaparib with topoisomerase I inhibitors. On the other hand, for temozolomide, PARP trapping was critical in addition to catalytic inhibition, consistent with the fact that olaparib was more effective than veliparib in combination with temozolomide. For cisplatin and etoposide, olaparib only showed no or a weak combination effect, which is consistent with the lack of involvement of PARP in the repair of cisplatin- and etoposide-induced lesions. Hence, we conclude that catalytic PARP inhibitors are highly effective in combination with camptothecins, whereas PARP inhibitors capable of PARP trapping are more effective with temozolomide. Our study provides insights in combination treatment rationales for different PARP inhibitors.

Footnotes

    • Received September 30, 2013.
    • Accepted March 10, 2014.
  • J.M. is a recipient of fellowships from the John Mung program (Kyoto University) and the Kyoto University Foundation. This work was supported by the Intramural Research Program of the National Institutes of Health [National Cancer Institute]; and the Center for Cancer Research [Grant Z01 BC 006150]. J.M. was supported by Japan Society for the Promotion of Science KAKENHI program [Grant 25740016]. J.J. was supported by the National Institutes of Health National Cancer Institute [Contract no. HHSN261200800001E].

  • dx.doi.org/10.1124/jpet.113.210146.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • U.S. Government work not protected by U.S. copyright
View Full Text

JPET 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

Journal of Pharmacology and Experimental Therapeutics: 349 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 349, Issue 3
1 Jun 2014
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • 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 Journal of Pharmacology and Experimental Therapeutics 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.
Rationale for Poly(ADP-ribose) Polymerase (PARP) Inhibitors in Combination Therapy with Camptothecins or Temozolomide Based on PARP Trapping versus Catalytic Inhibition
(Your Name) has forwarded a page to you from Journal of Pharmacology and Experimental Therapeutics
(Your Name) thought you would be interested in this article in Journal of Pharmacology and Experimental Therapeutics.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleChemotherapy, Antibiotics, and Gene Therapy

Rational Use of PARP Inhibitors in Combination Therapy

Junko Murai, Yiping Zhang, Joel Morris, Jiuping Ji, Shunichi Takeda, James H. Doroshow and Yves Pommier
Journal of Pharmacology and Experimental Therapeutics June 1, 2014, 349 (3) 408-416; DOI: https://doi.org/10.1124/jpet.113.210146

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Research ArticleChemotherapy, Antibiotics, and Gene Therapy

Rational Use of PARP Inhibitors in Combination Therapy

Junko Murai, Yiping Zhang, Joel Morris, Jiuping Ji, Shunichi Takeda, James H. Doroshow and Yves Pommier
Journal of Pharmacology and Experimental Therapeutics June 1, 2014, 349 (3) 408-416; DOI: https://doi.org/10.1124/jpet.113.210146
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
    • Acknowledgments
    • Authorship Contributions
    • Footnotes
    • Abbreviations
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Synergistic interactions of gemcitabine and FGFR inhibitors
  • Lysosomal Biogenesis and Hydroxychloroquine Disposition
  • Time-to-Event Analysis of Paclitaxel Peripheral Neuropathy
Show more Chemotherapy, Antibiotics, and Gene Therapy

Similar Articles

Advertisement
  • 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 JPET
  • 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
  • Molecular Pharmacology
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-0103 (Online)

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