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
Drug Metabolism & Disposition
  • 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
Drug Metabolism & Disposition

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 dmd on Facebook
  • Follow dmd on Twitter
  • Follow ASPET on LinkedIn
Research ArticleArticle

Differential Subcellular Distribution of Mitoxantrone in Relation to Chemosensitization in Two Human Breast Cancer Cell Lines

Sophie Vibet, Karine Mahéo, Jacques Goré, Pierre Dubois, Philippe Bougnoux and Igor Chourpa
Drug Metabolism and Disposition May 2007, 35 (5) 822-828; DOI: https://doi.org/10.1124/dmd.106.013474
Sophie Vibet
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Karine Mahéo
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jacques Goré
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Pierre Dubois
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Philippe Bougnoux
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Igor Chourpa
  • 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

The present work investigates the relationship between cancer cell chemosensitivity and subcellular distribution, molecular interaction, and metabolism of an anticancer drug. To get insights into this relationship, we took advantage of the differential sensitivity of two breast cancer cell lines, MDA-MB-231 and MCF-7, to anthracyclines, along with the property of docosahexaenoic acid (DHA, 22:6n-3), to differentially enhance their cytotoxic activity. The fluorescent drug mitoxantrone (MTX) was used because of the possibility to study its subcellular accumulation by confocal spectral imaging (CSI). The use of CSI allowed us to obtain semiquantitative maps of four intracellular species: nuclear MTX bound to DNA, MTX oxidative metabolite in endoplasmic reticulum, cytosolic MTX, and finally, MTX in a low polarity environment characteristic of membranes. MDA-MB-231 cells were found to be more sensitive to MTX (IC50 = 18 nM) than MCF-7 cells (IC50 = 196 nM). According to fluorescence levels, the nuclear and cytosolic MTX content was higher in MCF-7 than in MDA-MB-231 cells, indicating that mechanisms other than nuclear MTX accumulation account for chemosensitivity. In the cytosol, the relative proportion of oxidized MTX was higher in MDA-MB-231 (60%) than in MCF-7 (7%) cells. DHA sensitized MDA-MB-231 (∼4-fold) but not MCF-7 cells to MTX and increased MTX accumulation by 1.5-fold in MDA-MB-231 cells only. The DHA-stimulated accumulation of MTX was attributed mainly to the oxidative metabolite. Antioxidant N-acetyl-l-cysteine inhibited the DHA effect on both metabolite accumulation and cell sensitization to MTX. We conclude that drug metabolism and compartmentalization are associated with cell chemosensitization, and the related cytotoxicity mechanisms may involve oxidative stress.

Footnotes

  • This work was supported in part by grants from Ligue Nationale contre le Cancer (Comités d'Indre et Loire, Loir et Cher, Indre), by Institut National de la Santé et de la Recherche Médicale (Action Thématique Concertée “Nutrition”), by Conseil Régional (Région Centre), and by Cancéropôle Grand-Ouest. S.V. was the recipient of a fellowship from the Ministère de l'Enseignement Supérieur et de la Recherche.

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

  • doi:10.1124/dmd.106.013474.

  • ABBREVIATIONS: PUFA, polyunsaturated fatty acid; DHA, docosahexaenoic acid; MTX, mitoxantrone; ROS, reactive oxygen species; CSI, confocal spectral imaging; DMEM, Dulbecco's modified Eagle's medium; NAC, N-acetyl-l-cysteine; CM-H2DCFDA, 5(and 6)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate; a.u., arbitrary units.

    • Received October 24, 2006.
    • Accepted February 9, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
View Full Text

 

DMD 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

Drug Metabolism and Disposition: 35 (5)
Drug Metabolism and Disposition
Vol. 35, Issue 5
1 May 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 Drug Metabolism & Disposition 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.
Differential Subcellular Distribution of Mitoxantrone in Relation to Chemosensitization in Two Human Breast Cancer Cell Lines
(Your Name) has forwarded a page to you from Drug Metabolism & Disposition
(Your Name) thought you would be interested in this article in Drug Metabolism & Disposition.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleArticle

Differential Subcellular Distribution of Mitoxantrone in Relation to Chemosensitization in Two Human Breast Cancer Cell Lines

Sophie Vibet, Karine Mahéo, Jacques Goré, Pierre Dubois, Philippe Bougnoux and Igor Chourpa
Drug Metabolism and Disposition May 1, 2007, 35 (5) 822-828; DOI: https://doi.org/10.1124/dmd.106.013474

Citation Manager Formats

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

Differential Subcellular Distribution of Mitoxantrone in Relation to Chemosensitization in Two Human Breast Cancer Cell Lines

Sophie Vibet, Karine Mahéo, Jacques Goré, Pierre Dubois, Philippe Bougnoux and Igor Chourpa
Drug Metabolism and Disposition May 1, 2007, 35 (5) 822-828; DOI: https://doi.org/10.1124/dmd.106.013474
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
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • In Vivo Functional Effects of CYP2C9 M1L
  • Clearance pathways: fevipiprant with probenecid perpetrator
  • Predicting Volume of Distribution from In Vitro Parameters
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 DMD
  • Editorial Board
  • Instructions to Authors
  • Submit a Manuscript
  • Customized Alerts
  • RSS Feeds
  • Subscriptions
  • Permissions
  • Terms & Conditions of Use

ASPET's Other Journals

  • Journal of Pharmacology and Experimental Therapeutics
  • Molecular Pharmacology
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-009X (Online)

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