Document Detail

OSU-03012 promotes caspase-independent but PERK-, cathepsin B-, BID-, and AIF-dependent killing of transformed cells.
MedLine Citation:
PMID:  16622074     Owner:  NLM     Status:  MEDLINE    
We determined one mechanism by which the putative phosphoinositide-dependent kinase (PDK)-1 inhibitor 2-amino-N-{4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-phenyl}acetamide (OSU-03012) killed primary human glioma and other transformed cells. OSU-03012 caused a dose-dependent induction of cell death that was not altered by p53 mutation, expression of ERBB1 vIII, or loss of phosphatase and tensin homolog deleted on chromosome 10 function. OSU-03012 promoted cell killing to a greater extent in glioma cells than in nontransformed astrocytes. OSU-03012 and ionizing radiation caused an additive, caspase-independent elevation in cell killing in 96-h viability assays and true radiosensitization in colony formation assays. In a cell type-specific manner, combined exposure to OSU-03012 with a mitogen-activated protein kinase kinase 1/2 inhibitor, phosphoinositide 3-kinase/AKT inhibitors, or parallel molecular interventions resulted in a greater than additive induction of cell killing that was independent of AKT activity and caspase function. OSU-03012 lethality as a single agent or when combined with signaling modulators was not modified in cells lacking expression of BIM or of BAX/BAK. OSU-03012 promoted the release of cathepsin B from the lysosomal compartment and release of AIF from mitochondria. Loss of BH3-interacting domain (BID) function, overexpression of BCL(XL), and inhibition of cathepsin B function suppressed cell killing and apoptosis-inducing factor (AIF) release from mitochondria. In protein kinase R-like endoplasmic reticulum kinase-/- cells, the lethality of OSU-03012 was attenuated which correlated with reduced cleavage of BID and with suppression of cathepsin B and AIF release into the cytosol. Our data demonstrate that OSU-03012 promotes glioma cell killing that is dependent on endoplasmic reticulum stress, lysosomal dysfunction, and BID-dependent release of AIF from mitochondria, and whose lethality is enhanced by irradiation or by inhibition of protective signaling pathways.
Adly Yacoub; Margaret A Park; David Hanna; Young Hong; Clint Mitchell; Aditi P Pandya; Hisashi Harada; Garth Powis; Ching-Shih Chen; Costas Koumenis; 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:  2006-04-18
Journal Detail:
Title:  Molecular pharmacology     Volume:  70     ISSN:  0026-895X     ISO Abbreviation:  Mol. Pharmacol.     Publication Date:  2006 Aug 
Date Detail:
Created Date:  2006-07-19     Completed Date:  2006-08-28     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0035623     Medline TA:  Mol Pharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  589-603     Citation Subset:  IM    
Department of Biochemistry, Massey Cancer Center Virginia Commonwealth University, Richmond, VA 23298-0058, USA.
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MeSH Terms
1-Phosphatidylinositol 3-Kinase / physiology
Apoptosis Inducing Factor / physiology*
BH3 Interacting Domain Death Agonist Protein / physiology*
Caspases / physiology*
Cathepsin B / physiology*
Cell Line, Tumor
Enzyme Inhibitors / pharmacology*
Extracellular Signal-Regulated MAP Kinases / metabolism
Glioma / drug therapy,  pathology
Protein-Serine-Threonine Kinases / antagonists & inhibitors*
Proto-Oncogene Proteins c-akt / metabolism
Pyrazoles / pharmacology*
Reactive Oxygen Species / metabolism
Signal Transduction / drug effects
Sulfonamides / pharmacology*
eIF-2 Kinase / physiology*
Grant Support
Reg. No./Substance:
0/AIFM1 protein, human; 0/Apoptosis Inducing Factor; 0/BH3 Interacting Domain Death Agonist Protein; 0/BID protein, human; 0/Enzyme Inhibitors; 0/OSU 03012; 0/Pyrazoles; 0/Reactive Oxygen Species; 0/Sulfonamides; EC 2.7.1.-/3-phosphoinositide-dependent protein kinase; EC 3-Kinase; EC 2.7.10.-/PERK kinase; EC Kinases; EC Proteins c-akt; EC Kinase; EC Signal-Regulated MAP Kinases; EC 3.4.22.-/Caspases; EC B

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