Triciribine suppresses EGF-induced kinase activity and phosphorylation of Akt1, AKT2, and AKT3, but not the recombinant constitutively active AKT2 (Myr-AKT2), indicating that Triciribine does not directly inhibit Akt in vitro and that Triciribine neither functions as ATP competitor nor as the substrate competitor that binds to active site of Akt. Triciribine is highly selective for Akt over PI3K, PDK1, PKC, PKA, SGK, STAT3, ERK-1/2, and JNK. By selectively inhibiting the Akt pathway, Triciribine treatment leads to the suppression of cell growth and induction of apoptosis selectively in human cancer cells that harbor constitutively activated Akt due to overexpression of Akt or other genetic alterations such as PTEN mutation. Triciribine (1 μM) partially attenuates the phosphorylation levels of tuberin, Bad, GSK-3β, and AFX in OVCAR3 cells.
[2] Triciribine sensitizes PC-3 cells to TRAIL- and anti-CD95-induced apoptosis, whereas the cells remain resistant to DNA damaging chemotherapeutics.
[5] Triciribine binds Akt-derived pleckstrin homology (PH) domain with KD of 690 nM. In intact cells, Triciribine inhibits EGF-stimulated Akt recruitment to the plasma membrane, and that subsequent inhibition of Akt phosphorylation contributes to Triciribine antiproliferative and proapoptotic activities. Constitutively active Akt mutants, Akt1-T308D/S473D and myr-Akt1, but not the transforming mutant Akt1-E17K, are resistant to Triciribine and rescue from its inhibition of proliferation and induction of apoptosis.
[6] Triciribine shows strong inhibitory activity against K1861, KR158, KR130, and SF295 cells with GI50 of 1.73 μM, 0.36 μM, 1.07 μM, and 0.99 μM, respectively.
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