Identification of Akt-selective cytotoxic compounds that enhance cytotoxic responses to rapamycin

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 relat...

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Bibliographic Details
Published in:Cancer biology & therapy 2010-12, Vol.10 (12), p.1256-1261
Main Authors: Barger, Jennifer F., Gallo, Catherine A., Torni, Kyle A., Merk, Lisa, Seibel, William L., Nelson, Sandra, Plas, David R.
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - pharmacology
Apoptosis - drug effects
bcl-X Protein - genetics
bcl-X Protein - metabolism
Binding
Biology
Bioscience
Calcium
Cancer
Caspase 3 - metabolism
Cell
Cell Line
Cell Membrane - drug effects
Cell Survival - drug effects
Cycle
Dose-Response Relationship, Drug
Drug Discovery
Drug Screening Assays, Antitumor - methods
High-Throughput Screening Assays
Landes
Mice
Organogenesis
Oxazines
Phosphatidylinositol 3-Kinases - metabolism
Proteins
Proto-Oncogene Proteins c-akt - antagonists & inhibitors
Proto-Oncogene Proteins c-akt - metabolism
Signal Transduction - drug effects
Sirolimus - pharmacology
Xanthenes
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Summary: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.
ISSN:1538-4047
1555-8576
DOI:10.4161/cbt.10.12.13442