Document Detail


OSU-03012 interacts with lapatinib to kill brain cancer cells.
MedLine Citation:
PMID:  22990204     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
We have further defined mechanism(s) by which the drug OSU-03012 (OSU) kills brain cancer cells. OSU toxicity was enhanced by the HSP90 inhibitor 17-N-Allylamino-17-demethoxygeldanamycin (17AAG) that correlated with reduced expression of ERBB1 and ERBB2. Inhibition of the extrinsic apoptosis pathway blocked the interaction between 17AAG and OSU. OSU toxicity was enhanced by the inhibitor of ERBB1/2/4, lapatinib. Knock down of ERBB1/2/4 in a cell line specific fashion promoted OSU toxicity. Combined exposure of cells to lapatinib and OSU resulted in reduced AKT and ERK1/2 activity; expression of activated forms of AKT and to a lesser extent MEK1 protected cells from the lethal effects of the drug combination. Knock down of PTEN suppressed, and expression of PTEN enhanced, the lethal interaction between OSU and lapatinib. Downstream of PTEN, inhibition of mTOR recapitulated the effects of lapatinib. Knock down of CD95, NOXA, PUMA, BIK or AIF, suppressed lapatinib and OSU toxicity. Knock down of MCL-1 enhanced, and overexpression of MCL-1 suppressed, drug combination lethality. Lapatinib and OSU interacted in vivo to suppress the growth of established tumors. Collectively our data argue that the inhibition of ERBB receptor function represents a useful way to enhance OSU lethality in brain tumor cells.
Authors:
Laurence Booth; Nichola Cruickshanks; Thomas Ridder; Ching-Shih Chen; Steven Grant; 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:  2012-09-18
Journal Detail:
Title:  Cancer biology & therapy     Volume:  13     ISSN:  1555-8576     ISO Abbreviation:  Cancer Biol. Ther.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2013-01-09     Completed Date:  2013-06-26     Revised Date:  2013-12-04    
Medline Journal Info:
Nlm Unique ID:  101137842     Medline TA:  Cancer Biol Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1501-11     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Apoptosis / drug effects*
Apoptosis Regulatory Proteins / genetics
Benzoquinones / pharmacology
Brain Neoplasms / drug therapy*
Cell Line, Tumor
Drug Synergism
Genes, erbB-1
Heat-Shock Proteins / genetics
Humans
Lactams, Macrocyclic / pharmacology
Lipids
MAP Kinase Kinase 1
Membrane Proteins / genetics
Microtubule-Associated Proteins / genetics
Myeloid Cell Leukemia Sequence 1 Protein
PTEN Phosphohydrolase / genetics
Proto-Oncogene Proteins c-akt / drug effects,  metabolism
Proto-Oncogene Proteins c-bcl-2 / genetics
Pyrazoles / pharmacology*
Quinazolines / pharmacology*
RNA Interference
RNA, Small Interfering
Receptor, Epidermal Growth Factor / genetics
Receptor, erbB-2 / antagonists & inhibitors
Signal Transduction / drug effects
Sulfonamides / pharmacology*
Grant Support
ID/Acronym/Agency:
P01-CA104177/CA/NCI NIH HHS; R01 CA141703/CA/NCI NIH HHS; R01 CA150214/CA/NCI NIH HHS; R01 DK052825/DK/NIDDK NIH HHS; R01-CA141188/CA/NCI NIH HHS; R01-CA63753/CA/NCI NIH HHS; R01-CA77141/CA/NCI NIH HHS; R01-DK52825/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/ATG5 protein, human; 0/Apoptosis Regulatory Proteins; 0/BECN1 protein, human; 0/Benzoquinones; 0/Heat-Shock Proteins; 0/Lactams, Macrocyclic; 0/Lipids; 0/Lipofectamine; 0/Membrane Proteins; 0/Microtubule-Associated Proteins; 0/Myeloid Cell Leukemia Sequence 1 Protein; 0/OSU 03012; 0/Proto-Oncogene Proteins c-bcl-2; 0/Pyrazoles; 0/Quinazolines; 0/RNA, Small Interfering; 0/Sulfonamides; 0/molecular chaperone GRP78; 0VUA21238F/lapatinib; 169590-42-5/celecoxib; 4GY0AVT3L4/tanespimycin; EC 2.7.1.-/MAP2K1 protein, human; EC 2.7.10.1/ERBB2 protein, human; EC 2.7.10.1/Receptor, Epidermal Growth Factor; EC 2.7.10.1/Receptor, erbB-2; EC 2.7.10.1/receptor tyrosine-protein kinase erbB-4; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 2.7.12.2/MAP Kinase Kinase 1; EC 3.1.3.48/PTEN protein, human; EC 3.1.3.67/PTEN Phosphohydrolase
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