Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • 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
  • Submit
  • 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
    • Special Sections
    • 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
  • Submit
  • Visit jpet on Facebook
  • Follow jpet on Twitter
  • Follow jpet on LinkedIn
Research ArticleDrug Discovery and Translational Medicine

Inactivating PSMB5 Mutations and P-Glycoprotein (Multidrug Resistance-Associated Protein/ATP-Binding Cassette B1) Mediate Resistance to Proteasome Inhibitors: Ex Vivo Efficacy of (Immuno)Proteasome Inhibitors in Mononuclear Blood Cells from Patients with Rheumatoid Arthritis

Sue Ellen Verbrugge, Yehuda G. Assaraf, Ben A. C. Dijkmans, George L. Scheffer, Marjon Al, Debby den Uyl, Ruud Oerlemans, Elena T. Chan, Christopher J. Kirk, Godefridus J. Peters, Joost W. van der Heijden, Tanja D. de Gruijl, Rik J. Scheper and Gerrit Jansen
Journal of Pharmacology and Experimental Therapeutics April 2012, 341 (1) 174-182; DOI: https://doi.org/10.1124/jpet.111.187542
Sue Ellen Verbrugge
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yehuda G. Assaraf
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ben A. C. Dijkmans
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
George L. Scheffer
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Marjon Al
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Debby den Uyl
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ruud Oerlemans
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Elena T. Chan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Christopher J. Kirk
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Godefridus J. Peters
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Joost W. van der Heijden
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Tanja D. de Gruijl
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Rik J. Scheper
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Gerrit Jansen
  • 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

Bortezomib (BTZ), a registered proteasome inhibitor (PI) for multiple myeloma, has also been proposed as a potential antirheumatic agent. Its reported side effects, however, make it unappealing for long-term administration, and resistance may also develop. To overcome this, second-generation PIs became available. Here, we investigated whether a novel class of peptide epoxyketone-based PIs, including carfilzomib, N-((S)-3-methoxy-1-(((S)-3-methoxy-1-(((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)-2-methylthiazole-5-carboxamide (ONX0912), and (S)-3-(4-methoxyphenyl)-N-((S)-1-((S)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)propanamido)propanamide (ONX0914), might escape two established BTZ-resistance mechanisms: 1) mutations in the proteasome β5 subunit (PSMB5) targeted by these PIs, and 2) drug efflux mediated by ATP-binding cassette transporters. THP1 myeloid sublines with acquired resistance to BTZ (54- to 235-fold) caused by mutations in the PSMB5 gene displayed marked cross-resistance but less pronounced cross-resistance to carfilzomib (9- to 32-fold), ONX0912 (39- to 62-fold), and ONX0914 (27- to 97-fold). As for ATP-binding cassette transporter-mediated efflux, lymphoid CEM/VLB cells with P-glycoprotein (Pgp)/multidrug resistance 1 overexpression exhibited substantial resistance to carfilzomib (114-fold), ONX0912 (23-fold), and ONX0914 (162-fold), whereas less resistance to BTZ (4.5-fold) was observed. Consistently, β5 subunit-associated chymotrypsin-like proteasome activity was significantly less inhibited in these CEM/VLB cells. Ex vivo analysis of peripheral blood mononuclear cells from therapy-naive patients with rheumatoid arthritis revealed that, although basal Pgp levels were low, P-glycoprotein expression compromised the inhibitory effect of carfilzomib and ONX0914. However, the use of P121 (reversin 121), a Pgp transport inhibitor, restored parental cell inhibitory levels in both CEM/VLB cells and peripheral blood mononuclear cells. These results indicate that the pharmacologic activity of these PIs may be hindered by drug resistance mechanisms involving PSMB5 mutations and PI extrusion via Pgp.

Footnotes

  • This study was supported by the Cancer Center Amsterdam/VU Institute of Cancer and Immunology [Grant 07/36]. Y.G.A. is a recipient of Visiting Professor Fellowships from the Royal Netherlands Academy of Arts and Sciences and the Netherlands Organization for Scientific Research.

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

    http://dx.doi.org/10.1124/jpet.111.187542.

  • ABBREVIATIONS:

    PI
    proteasome inhibitor
    PSMB5
    proteasome β5 subunit
    BTZ
    bortezomib
    ONX0912
    N-((S)-3-methoxy-1-(((S)-3-methoxy-1-(((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)-2-methylthiazole-5-carboxamide
    ONX0914
    (S)-3-(4-methoxyphenyl)-N-((S)-1-((S)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)propanamido) propanamide
    ABC
    ATP-binding cassette
    MDR
    multidrug resistance
    MRP
    multidrug resistance-associated protein
    Pgp
    P-glycoprotein
    BCRP
    breast cancer resistance protein
    RA
    rheumatoid arthritis
    PBMC
    peripheral blood mononuclear cell
    HEK
    human embryonic kidney
    WT
    wild type.

  • Received September 1, 2011.
  • Accepted January 6, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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: 341 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 341, Issue 1
1 Apr 2012
  • 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.
Inactivating PSMB5 Mutations and P-Glycoprotein (Multidrug Resistance-Associated Protein/ATP-Binding Cassette B1) Mediate Resistance to Proteasome Inhibitors: Ex Vivo Efficacy of (Immuno)Proteasome Inhibitors in Mononuclear Blood Cells from Patients with…
(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 ArticleDrug Discovery and Translational Medicine

Resistance to Epoxyketone-Based Proteasome Inhibitors

Sue Ellen Verbrugge, Yehuda G. Assaraf, Ben A. C. Dijkmans, George L. Scheffer, Marjon Al, Debby den Uyl, Ruud Oerlemans, Elena T. Chan, Christopher J. Kirk, Godefridus J. Peters, Joost W. van der Heijden, Tanja D. de Gruijl, Rik J. Scheper and Gerrit Jansen
Journal of Pharmacology and Experimental Therapeutics April 1, 2012, 341 (1) 174-182; DOI: https://doi.org/10.1124/jpet.111.187542

Citation Manager Formats

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

Share
Research ArticleDrug Discovery and Translational Medicine

Resistance to Epoxyketone-Based Proteasome Inhibitors

Sue Ellen Verbrugge, Yehuda G. Assaraf, Ben A. C. Dijkmans, George L. Scheffer, Marjon Al, Debby den Uyl, Ruud Oerlemans, Elena T. Chan, Christopher J. Kirk, Godefridus J. Peters, Joost W. van der Heijden, Tanja D. de Gruijl, Rik J. Scheper and Gerrit Jansen
Journal of Pharmacology and Experimental Therapeutics April 1, 2012, 341 (1) 174-182; DOI: https://doi.org/10.1124/jpet.111.187542
Reddit logo Twitter logo Facebook 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

Related Articles

Cited By...

More in this TOC Section

  • TRPA1 inhibitors ameliorate tear gas-induced skin injuries
  • Treatment of SM Corneal Injury by Augmenting the DDR
  • Symptomatic reversal of botulism by aminopyridines
Show more Drug Discovery and Translational Medicine

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 © 2023 by the American Society for Pharmacology and Experimental Therapeutics