Document Detail


Inhibitors of cathepsins B and L induce autophagy and cell death in neuroblastoma cells.
MedLine Citation:
PMID:  22549440     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
This study was designed to test the hypothesis that specific inhibition of cathepsins B and L will cause death of neuroblastoma cells. Five compounds that differ in mode and rate of inhibition of these two enzymes were all shown to cause neuroblastoma cell death. Efficacy of the different compounds was related to their ability to inhibit the activity of the isolated enzymes. A dose- and time-response for induction of cell death was demonstrated for each compound. A proteomic study showed that inhibitor treatment caused an increase of markers of cell stress, including induction of levels of the autophagy marker, LC-3-II. Levels of this marker protein were highest at cytotoxic inhibitor concentrations, implicating autophagy in the cell death process. An in vivo mouse model showed that one of these inhibitors markedly impaired tumor growth. It is concluded that development of drugs to target these two proteases may provide a novel approach to treating neuroblastoma.
Authors:
Donna M Cartledge; Rita Colella; Lisa Glazewski; Guizhen Lu; Robert W Mason
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-05-02
Journal Detail:
Title:  Investigational new drugs     Volume:  31     ISSN:  1573-0646     ISO Abbreviation:  Invest New Drugs     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-01-24     Completed Date:  2013-07-31     Revised Date:  2014-08-01    
Medline Journal Info:
Nlm Unique ID:  8309330     Medline TA:  Invest New Drugs     Country:  United States    
Other Details:
Languages:  eng     Pagination:  20-9     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Antineoplastic Agents / pharmacology,  therapeutic use*
Cathepsin B / antagonists & inhibitors*
Cathepsin L / antagonists & inhibitors*
Cell Death / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Humans
Mice
Mice, Inbred BALB C
Mice, Mutant Strains
Neuroblastoma / drug therapy*,  pathology
Xenograft Model Antitumor Assays
Grant Support
ID/Acronym/Agency:
8P20GM103464/GM/NIGMS NIH HHS; P20 GM103446/GM/NIGMS NIH HHS; P20 GM103464/GM/NIGMS NIH HHS; P20RR016472/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; EC 3.4.22.1/CTSB protein, human; EC 3.4.22.1/Cathepsin B; EC 3.4.22.15/CTSL1 protein, human; EC 3.4.22.15/Cathepsin L
Comments/Corrections

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