Triciribine, also known as API-2, NSC 154020, is a cell-permeable tricyclic nucleoside that inhibits the phosphorylation, activation, and signalling of Akt-1, -2, and -3. Akt-1, -2, and -3 are serine/threonine protein kinases in the phosphatidylinositol 3 (PI3)-kinase signalling pathway that play a critical role in the regulation of cell proliferation and survival. Triciribine induced autophagy, which could be interpreted as a defensive mechanism, because an autophagy inhibitor (chloroquine) increased triciribine-induced apoptosis. In vitro, Triciribine (API-2) significantly inhibits Akt-overexpressing human cancer cell lines growth with 50% inhibition at ~5-10 µM. It also inhibits DNA synthesis and displays antiviral activity against HIV-1 and -2. Combinations of triciribine with classic inhibitors targeting other molecules of the PI3K-AKT-pathway led to synergistic anti-proliferative effects.
|Cell lines||LNCaP, PC-3, OVCAR3, OVCA8, PANC1, MDA-MB-468, and WM35 cells line|
|Preparation method||Screening for Inhibition of Akt-Transformed Cell Growth.
AKT2 transformed NIH3T3 cells or LXSN vector-transfected NIH3T3 control cells (4) were plated into 96-well tissue culture plate. After treatment with 5 μM NCI Diversity Set compound, cell growth was detected with CellTier 96 One Solution Cell Proliferation kit (Promega). Compounds that inhibit growth in AKT2-transformed but not LXSN-transfected NIH3T3 cells were considered as candidates of Akt inhibitor and subjected to additional analysis.
|Incubation time||24 and 48 h|
|Animal models||Nude Mouse Tumor Xenograft Model|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
AKT inhibition by triciribine alone or as combination therapy for growth control of gastroenteropancreatic neuroendocrine tumors.
Gloesenkamp CR, et al. Int J Oncol. 2012 Mar;40(3):876-88. PMID: 22075556.
Preclinical testing of the Akt inhibitor triciribine in T-cell acute lymphoblastic leukemia.
Evangelisti C, et al. J Cell Physiol. 2011 Mar;226(3):822-31. PMID: 20857426.
Akt/protein kinase B signaling inhibitor-2, a selective small molecule inhibitor of Akt signaling with antitumor activity in cancer cells overexpressing Akt.
Yang L, et al. Cancer Res. 2004 Jul 1;64(13):4394-9. PMID: 15231645.
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|AKT inhibitor VIII
Akt Inhibitor VIII is a cell-permeable quinoxaline compound that has been shown to potently, selectively, allosterically, and reversibly inhibit Akt1, Akt2, and Akt3 activity (IC50 = 58 nM, 210 nM, and 2.12 μM; respectively).
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