Document Detail


Identification of Akt-selective cytotoxic compounds that enhance cytotoxic responses to rapamycin.
MedLine Citation:
PMID:  20935504     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
We performed a high-throughput screen to identify compounds with a selective ability to induce apoptosis in Akt-expressing cells without disrupting Bcl-xL-dependent survival. Results showed that a screening strategy based on Alamar Blue underrepresented the viability of Bcl-xL-expressing cells relative to Akt-expressing cells, possibly due to metabolic differences between the two cell survival programs. Using an alternative screen based on plasma membrane integrity, we identified several compounds that target Akt-dependent survival without toxic effect to Bcl-xL-dependent survival. These compounds enhanced the cytotoxic potential of rapamycin, a chemotherapeutic that inhibits survival signaling downstream of Akt. The results demonstrate a screening method and the subsequent identification of two compounds with selective activity in counteracting Akt-dependent cell survival.
Authors:
Jennifer F Barger; Catherine A Gallo; Kyle A Torni; Lisa Merk; William L Seibel; Sandra Nelson; David R Plas
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-12-15
Journal Detail:
Title:  Cancer biology & therapy     Volume:  10     ISSN:  1555-8576     ISO Abbreviation:  Cancer Biol. Ther.     Publication Date:  2010 Dec 
Date Detail:
Created Date:  2011-01-13     Completed Date:  2011-07-26     Revised Date:  2013-02-05    
Medline Journal Info:
Nlm Unique ID:  101137842     Medline TA:  Cancer Biol Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1256-61     Citation Subset:  IM    
Affiliation:
Department of Cancer and Cell Biology, University of Cincinnati, Cincinnati, OH, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects*
Caspase 3 / metabolism
Cell Line
Cell Membrane / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Discovery
Drug Screening Assays, Antitumor / methods
High-Throughput Screening Assays*
Mice
Oxazines
Phosphatidylinositol 3-Kinases / metabolism
Proto-Oncogene Proteins c-akt / antagonists & inhibitors,  metabolism*
Signal Transduction / drug effects
Sirolimus / pharmacology*
Xanthenes
bcl-X Protein / genetics,  metabolism*
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Oxazines; 0/Xanthenes; 0/bcl-X Protein; 53123-88-9/Sirolimus; 550-82-3/resazurin; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 3.4.22.-/Caspase 3
Comments/Corrections
Comment In:
Cancer Biol Ther. 2010 Dec 15;10(12):1262-5   [PMID:  20935459 ]

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


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