Document Detail


OSU-03012 enhances Ad.7-induced GBM cell killing via ER stress and autophagy and by decreasing expression of mitochondrial protective proteins.
MedLine Citation:
PMID:  20107314     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The present studies focused on determining whether the autophagy-inducing drug OSU-03012 (AR-12) could enhance the toxicity of recombinant adenoviral delivery of melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24) in glioblastoma multiforme (GBM) cells. The toxicity of a recombinant adenovirus to express MDA-7/IL-24 (Ad.mda-7) was enhanced by OSU-03012 in a diverse panel of primary human GBM cells. The enhanced toxicity correlated with reduced ERK1/2 phosphorylation and expression of MCL-1 and BCL-XL, and was blocked by molecular activation of ERK1/2 and by inhibition of the intrinsic, but not the extrinsic, apoptosis pathway.  Both OSU-03012 and expression of MDA-7/IL-24 increased phosphorylation of PKR-like endoplasmic reticulum kinase (PERK) that correlated with increased levels of autophagy and expression of dominant negative PERK blocked autophagy induction and tumor cell death. Knockdown of ATG5 or Beclin1 suppressed OSU-03012 enhanced MDA-7/IL-24-induced autophagy and blocked the lethal interaction between the two agents. Ad.mda-7-infected GBM cells secreted MDA-7/IL-24 into the growth media and this conditioned media induced expression of MDA-7/IL-24 in uninfected GBM cells. OSU-03012 interacted with conditioned media to kill GBM cells and knockdown of MDA-7/IL-24 in these cells suppressed tumor cell killing. Collectively, our data demonstrate that the induction of autophagy and mitochondrial dysfunction by a combinatorial treatment approach represents a potentially viable strategy to kill primary human GBM cells.
Authors:
Hossein A Hamed; Adly Yacoub; Margaret A Park; Patrick Eulitt; Devanand Sarkar; Igor P Dimitrie; Ching-Shih Chen; Steven Grant; David T Curiel; Paul B Fisher; Paul Dent
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2010-04-01
Journal Detail:
Title:  Cancer biology & therapy     Volume:  9     ISSN:  1555-8576     ISO Abbreviation:  Cancer Biol. Ther.     Publication Date:  2010 Apr 
Date Detail:
Created Date:  2010-11-24     Completed Date:  2011-03-10     Revised Date:  2014-09-14    
Medline Journal Info:
Nlm Unique ID:  101137842     Medline TA:  Cancer Biol Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  526-36     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adenoviridae / genetics
Apoptosis / drug effects
Autophagy*
Blotting, Western
Brain Neoplasms / genetics,  pathology,  therapy
Cell Line, Tumor
Cell Proliferation / drug effects
Combined Modality Therapy
Drug Synergism
Endoplasmic Reticulum / metabolism,  pathology*
Flow Cytometry
Genetic Therapy*
Glioblastoma / genetics,  pathology*,  therapy*
Humans
In Situ Nick-End Labeling
Interleukins / genetics
Mitochondrial Proteins / metabolism*
Phosphorylation / drug effects
Pyrazoles / therapeutic use*
Sulfonamides / therapeutic use*
eIF-2 Kinase / metabolism
Grant Support
ID/Acronym/Agency:
P01 CA104177/CA/NCI NIH HHS; P01-CA104177/CA/NCI NIH HHS; P01-NS031492/NS/NINDS NIH HHS; R01 CA108520/CA/NCI NIH HHS; R01 CA141703/CA/NCI NIH HHS; R01 DK052825/DK/NIDDK NIH HHS; R01-CA097318/CA/NCI NIH HHS; R01-CA108325/CA/NCI NIH HHS; R01-CA134721/CA/NCI NIH HHS; R01-DK52825/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Interleukins; 0/Mitochondrial Proteins; 0/OSU 03012; 0/Pyrazoles; 0/Sulfonamides; 0/interleukin-24; EC 2.7.10.-/PERK kinase; EC 2.7.11.1/eIF-2 Kinase
Comments/Corrections
Comment In:
Cancer Biol Ther. 2010 Apr 1;9(7):537-8   [PMID:  20234182 ]

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