Document Detail


The Akt inhibitor triciribine sensitizes prostate carcinoma cells to TRAIL-induced apoptosis.
MedLine Citation:
PMID:  19422047     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Aberrant PI3K/Akt signaling has been implicated in many human cancers, including prostate carcinomas. Currently different therapeutic strategies target the inhibition of this survival pathway. The nucleoside analog triciribine (TCN), which was initially described as a DNA synthesis inhibitor, has recently been shown to function as an inhibitor of Akt. Here, we demonstrate that TCN inhibits Akt phosphorylation at Thr308 and Ser473 and Akt activity in the human prostate cancer cell line PC-3. In addition, TCN sensitized PC-3 cells to TRAIL- and anti-CD95-induced apoptosis, whereas the cells remained resistant to DNA damaging chemotherapeutics. The observed sensitization essentially depended on the phosphorylation status of Akt. Thus, prostate cancer cell lines displaying constitutively active Akt, e.g. PC-3 or LNCaP, were sensitized to death receptor-induced apoptosis. Most importantly with respect to therapeutic application, derivatives of both TCN and TRAIL are already tested in current clinical trials. Therefore, this combinatorial treatment might open a promising therapeutic approach for the elimination of hormone-refractory prostate cancers, which are largely resistant to conventional DNA damaging anticancer drugs or irradiation.
Authors:
Alexandra Dieterle; Ronald Orth; Merle Daubrawa; Antje Grotemeier; Sebastian Alers; Susanne Ullrich; Reiner Lammers; Sebastian Wesselborg; Björn Stork
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  International journal of cancer. Journal international du cancer     Volume:  125     ISSN:  1097-0215     ISO Abbreviation:  Int. J. Cancer     Publication Date:  2009 Aug 
Date Detail:
Created Date:  2009-06-22     Completed Date:  2009-08-04     Revised Date:  2012-06-22    
Medline Journal Info:
Nlm Unique ID:  0042124     Medline TA:  Int J Cancer     Country:  United States    
Other Details:
Languages:  eng     Pagination:  932-41     Citation Subset:  IM    
Affiliation:
Department of Internal Medicine I, University of Tübingen, Tübingen, Germany.
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MeSH Terms
Descriptor/Qualifier:
Apoptosis / drug effects*
BH3 Interacting Domain Death Agonist Protein / metabolism
Caspases / metabolism
Drug Resistance, Neoplasm / drug effects*
Humans
Immunoblotting
Male
Mitochondria / drug effects
Phosphorylation / drug effects
Prostatic Neoplasms / metabolism,  pathology*
Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
RNA, Small Interfering / pharmacology
Ribonucleosides / pharmacology*
TNF-Related Apoptosis-Inducing Ligand / genetics,  metabolism*
Trail Making Test
Tumor Cells, Cultured
Chemical
Reg. No./Substance:
0/BH3 Interacting Domain Death Agonist Protein; 0/BID protein, human; 0/RNA, Small Interfering; 0/Ribonucleosides; 0/TNF-Related Apoptosis-Inducing Ligand; 0/TNFSF10 protein, human; 35943-35-2/triciribine; EC 2.7.11.1/AKT1 protein, human; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 3.4.22.-/Caspases

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


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