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
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
    • 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 molpharm on Facebook
  • Follow molpharm on Twitter
  • Follow molpharm on LinkedIn
Research ArticleArticle

Resveratrol Sensitizes Acute Myelogenous Leukemia Cells to Histone Deacetylase Inhibitors through Reactive Oxygen Species-Mediated Activation of the Extrinsic Apoptotic Pathway

Alae Yaseen, Shuang Chen, Stefanie Hock, Roberto Rosato, Paul Dent, Yun Dai and Steven Grant
Molecular Pharmacology December 2012, 82 (6) 1030-1041; DOI: https://doi.org/10.1124/mol.112.079624
Alae Yaseen
Departments of Medicine (A.Y., S.C., S.H., R.R., Y.D., S.G.), Neurosurgery (P.D.), Biochemistry (S.G.), Pharmacology (S.G.), and Human and Molecular Genetics (S.G.) and Massey Cancer Center (A.Y., S.C., S.H., R.R., P.D., Y.D., S.G.), Virginia Commonwealth University Health Sciences Center, Richmond, Virginia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Shuang Chen
Departments of Medicine (A.Y., S.C., S.H., R.R., Y.D., S.G.), Neurosurgery (P.D.), Biochemistry (S.G.), Pharmacology (S.G.), and Human and Molecular Genetics (S.G.) and Massey Cancer Center (A.Y., S.C., S.H., R.R., P.D., Y.D., S.G.), Virginia Commonwealth University Health Sciences Center, Richmond, Virginia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Stefanie Hock
Departments of Medicine (A.Y., S.C., S.H., R.R., Y.D., S.G.), Neurosurgery (P.D.), Biochemistry (S.G.), Pharmacology (S.G.), and Human and Molecular Genetics (S.G.) and Massey Cancer Center (A.Y., S.C., S.H., R.R., P.D., Y.D., S.G.), Virginia Commonwealth University Health Sciences Center, Richmond, Virginia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Roberto Rosato
Departments of Medicine (A.Y., S.C., S.H., R.R., Y.D., S.G.), Neurosurgery (P.D.), Biochemistry (S.G.), Pharmacology (S.G.), and Human and Molecular Genetics (S.G.) and Massey Cancer Center (A.Y., S.C., S.H., R.R., P.D., Y.D., S.G.), Virginia Commonwealth University Health Sciences Center, Richmond, Virginia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Paul Dent
Departments of Medicine (A.Y., S.C., S.H., R.R., Y.D., S.G.), Neurosurgery (P.D.), Biochemistry (S.G.), Pharmacology (S.G.), and Human and Molecular Genetics (S.G.) and Massey Cancer Center (A.Y., S.C., S.H., R.R., P.D., Y.D., S.G.), Virginia Commonwealth University Health Sciences Center, Richmond, Virginia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yun Dai
Departments of Medicine (A.Y., S.C., S.H., R.R., Y.D., S.G.), Neurosurgery (P.D.), Biochemistry (S.G.), Pharmacology (S.G.), and Human and Molecular Genetics (S.G.) and Massey Cancer Center (A.Y., S.C., S.H., R.R., P.D., Y.D., S.G.), Virginia Commonwealth University Health Sciences Center, Richmond, Virginia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Steven Grant
Departments of Medicine (A.Y., S.C., S.H., R.R., Y.D., S.G.), Neurosurgery (P.D.), Biochemistry (S.G.), Pharmacology (S.G.), and Human and Molecular Genetics (S.G.) and Massey Cancer Center (A.Y., S.C., S.H., R.R., P.D., Y.D., S.G.), Virginia Commonwealth University Health Sciences Center, Richmond, Virginia
  • 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

Histone deacetylase inhibitors (HDACIs) activate the prosurvival nuclear factor-κB (NF-κB) pathway by hyperacetylating RelA/p65, whereas the chemopreventive agent resveratrol inhibits NF-κB by activating the class III histone deacetylase Sirt1. Interactions between resveratrol and pan-HDACIs (vorinostat and panobinostat) were examined in human acute myelogenous leukemia (AML) cells. Pharmacologically achievable resveratrol concentrations (25–50 μM) synergistically potentiated HDACI lethality in AML cell lines and primary AML blasts. Resveratrol antagonized RelA acetylation and NF-κB activation in HDACI-treated cells. However, short hairpin RNA Sirt1 knockdown failed to modify HDACI sensitivity, which suggests that factors other than or in addition to Sirt1 activation contribute to resveratrol/HDACI interactions. These interactions were associated with death receptor 5 (DR5) up-regulation and caspase-8 activation, whereas cells expressing dominant-negative caspase-8 were substantially protected from resveratrol/HDACI treatment, which suggests a significant functional role for the extrinsic apoptotic pathway in lethality. Exposure to resveratrol with HDACI induced sustained reactive oxygen species (ROS) generation, which was accompanied by increased levels of DNA double-strand breaks, as reflected in γH2A.X and comet assays. The free radical scavenger Mn(III)tetrakis(4-benzoic acid)porphyrin chloride blocked ROS generation, DR5 up-regulation, caspase-8 activation, DNA damage, and apoptosis, which indicates a primary role for oxidative injury in lethality. Analyses of cell-cycle progression and 5-ethynyl-2′-deoxyuridine incorporation through flow cytometry revealed that resveratrol induced S-phase accumulation; this effect was abrogated by HDACI coadministration, which suggests that cells undergoing DNA synthesis may be particularly vulnerable to HDACI lethality. Collectively, these findings indicate that resveratrol interacts synergistically with HDACIs in AML cells through multiple ROS-dependent actions, including death receptor up-regulation, extrinsic apoptotic pathway activation, and DNA damage induction. They also raise the possibility that S-phase cells may be particularly susceptible to these actions.

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 [Grants CA93738, CA100866, 1P50-CA142509-01, 1P50-CA130805-01]; the Leukemia and Lymphoma Society of America [Grant 6181-10]; the V Foundation; and the Multiple Myeloma Research Foundation.

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

    http://dx.doi.org/10.1124/mol.112.079624.

  • ABBREVIATIONS:

    HDACI
    histone deacetylase inhibitor
    HDAC
    histone deacetylase
    PI
    propidium iodide
    AML
    acute myelogenous leukemia
    shRNA
    short hairpin RNA
    ELISA
    enzyme-linked immunosorbent assay
    ML171
    2-acetylphenothiazine
    MnTBAP
    Mn(III)tetrakis(4-benzoic acid)porphyrin chloride
    ROS
    reactive oxygen species
    DR5
    death receptor 5
    NF-κB
    nuclear factor-κB
    IKK
    IκB kinase
    NOX
    NADPH oxidase
    PARP
    poly(ADP-ribose) polymerase
    EdU
    5-ethynyl-2′-deoxyuridine.

  • Received April 25, 2012.
  • Accepted August 23, 2012.
  • Copyright © 2012 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: 82 (6)
Molecular Pharmacology
Vol. 82, Issue 6
1 Dec 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 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.
Resveratrol Sensitizes Acute Myelogenous Leukemia Cells to Histone Deacetylase Inhibitors through Reactive Oxygen Species-Mediated Activation of the Extrinsic Apoptotic Pathway
(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

Resveratrol Increases HDAC Inhibitor Anti-AML Activity

Alae Yaseen, Shuang Chen, Stefanie Hock, Roberto Rosato, Paul Dent, Yun Dai and Steven Grant
Molecular Pharmacology December 1, 2012, 82 (6) 1030-1041; DOI: https://doi.org/10.1124/mol.112.079624

Citation Manager Formats

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

Share
Research ArticleArticle

Resveratrol Increases HDAC Inhibitor Anti-AML Activity

Alae Yaseen, Shuang Chen, Stefanie Hock, Roberto Rosato, Paul Dent, Yun Dai and Steven Grant
Molecular Pharmacology December 1, 2012, 82 (6) 1030-1041; DOI: https://doi.org/10.1124/mol.112.079624
del.icio.us logo Digg logo Reddit logo Twitter 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
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • The binding site for KCI807 in the androgen receptor
  • Fatty acid amide hydrolase in cisplatin nephrotoxicity
  • eCB Signaling System in hiPSC-Derived Neuronal Cultures
Show more Articles

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 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 © 2023 by the American Society for Pharmacology and Experimental Therapeutics