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

• 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
• ISSN: 1538-4047; 1555-8576
• DOI: 10.4161/cbt.10.12.13442

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.