Document Detail


ROS inhibitor N-acetyl-L-cysteine antagonizes the activity of proteasome inhibitors.
MedLine Citation:
PMID:  23772801     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
NAC (N-acetyl-L-cysteine) is commonly used to identify and test ROS (reactive oxygen species) inducers, and to inhibit ROS. In the present study, we identified inhibition of proteasome inhibitors as a novel activity of NAC. Both NAC and catalase, another known scavenger of ROS, similarly inhibited ROS levels and apoptosis associated with H₂O₂. However, only NAC, and not catalase or another ROS scavenger Trolox, was able to prevent effects linked to proteasome inhibition, such as protein stabilization, apoptosis and accumulation of ubiquitin conjugates. These observations suggest that NAC has a dual activity as an inhibitor of ROS and proteasome inhibitors. Recently, NAC was used as a ROS inhibitor to functionally characterize a novel anticancer compound, piperlongumine, leading to its description as a ROS inducer. In contrast, our own experiments showed that this compound depicts features of proteasome inhibitors including suppression of FOXM1 (Forkhead box protein M1), stabilization of cellular proteins, induction of ROS-independent apoptosis and enhanced accumulation of ubiquitin conjugates. In addition, NAC, but not catalase or Trolox, interfered with the activity of piperlongumine, further supporting that piperlongumine is a proteasome inhibitor. Most importantly, we showed that NAC, but not other ROS scavengers, directly binds to proteasome inhibitors. To our knowledge, NAC is the first known compound that directly interacts with and antagonizes the activity of proteasome inhibitors. Taken together, the findings of the present study suggest that, as a result of the dual nature of NAC, data interpretation might not be straightforward when NAC is utilized as an antioxidant to demonstrate ROS involvement in drug-induced apoptosis.
Authors:
Marianna Halasi; Ming Wang; Tanmay S Chavan; Vadim Gaponenko; Nissim Hay; Andrei L Gartel
Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  The Biochemical journal     Volume:  454     ISSN:  1470-8728     ISO Abbreviation:  Biochem. J.     Publication Date:  2013 Sep 
Date Detail:
Created Date:  2013-08-12     Completed Date:  2013-11-04     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  2984726R     Medline TA:  Biochem J     Country:  England    
Other Details:
Languages:  eng     Pagination:  201-8     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Acetylcysteine / metabolism,  pharmacology*
Antineoplastic Agents, Phytogenic / antagonists & inhibitors,  pharmacology
Apoptosis / drug effects
Catalase / genetics,  metabolism
Cell Line, Tumor
Chromans / antagonists & inhibitors,  metabolism,  pharmacology
Cytomegalovirus / enzymology
Dioxolanes / antagonists & inhibitors,  pharmacology
Forkhead Transcription Factors / antagonists & inhibitors,  genetics,  metabolism
Free Radical Scavengers / metabolism,  pharmacology*
Humans
Hydrogen Peroxide / antagonists & inhibitors,  pharmacology
Oxidants / antagonists & inhibitors,  pharmacology
Proteasome Endopeptidase Complex / drug effects*,  metabolism
Proteasome Inhibitors / chemistry,  metabolism,  pharmacology*
Protein Stability / drug effects
Reactive Oxygen Species / antagonists & inhibitors*,  metabolism
Recombinant Proteins / antagonists & inhibitors,  metabolism
Ubiquitinated Proteins / metabolism
Viral Proteins / genetics,  metabolism
Grant Support
ID/Acronym/Agency:
1R01CA129414/CA/NCI NIH HHS; AG016927/AG/NIA NIH HHS; CA090764/CA/NCI NIH HHS; R01 AG016927/AG/NIA NIH HHS; R01 CA090764/CA/NCI NIH HHS; R01CA135341/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents, Phytogenic; 0/Chromans; 0/Dioxolanes; 0/FOXM1 protein, human; 0/Forkhead Transcription Factors; 0/Free Radical Scavengers; 0/Oxidants; 0/Proteasome Inhibitors; 0/Reactive Oxygen Species; 0/Recombinant Proteins; 0/Ubiquitinated Proteins; 0/Viral Proteins; 56305-04-5/6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid; BBX060AN9V/Hydrogen Peroxide; EC 1.11.1.6/Catalase; EC 3.4.25.1/Proteasome Endopeptidase Complex; HN39MC8KIO/piperlonguminine; WYQ7N0BPYC/Acetylcysteine

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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