Biological Activity
|
Description
|
Triciribine phosphate (TCN-P, NSC-280594, API-2) is a potent Akt inhibitor with IC50 of 130 nM. |
Targets
|
Akt |
|
|
|
|
|
IC50 |
130 nM [1] |
|
|
|
|
|
In Vitro
|
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. [1] |
In Vivo
|
Consistent with the inhibition of Akt activity, administration of Triciribine at low dose potently inhibits the growth of Akt-overexpressing tumor cells in nude mice including OVCAR3, OVCAR8, and PANC1 by 90%, 88%, and 80%, respectively, while has little effect on the growth of OVCAR5 and COLO357 cells in nude mice, which express low levels of Akt. [2] |
Clinical Trials
|
A Phase I study of Triciribine phosphate in adult subjects with metastatic cancer which have activated akt demonstrated by immunohistochemistry has been completed. |
Features
|
|
Combination Therapy
|
Description
|
Triciribine in combination with trastuzumab inhibits cell growth and induces cell death in breast cancer cells that are previously trastuzumab resistant. In a xenograft model, Triciribine in combination with trastuzumab dramatically inhibits tumor growth. [3] Triciribine treatment sensitizes the resistant HT29 cells to cisplatin. [4] Combination treatment with triciribine and gemcitabine has a better effect on tumor inhibition than either drug alone and that the inhibition effect is more significant in shFKBP5 xenograft mice than wt mice. [7] |
Protocol
|
Kinase Assay
[1]
|
Inhibition of phospho-Akt and phospho-p70S6K (Thr389) |
KR158 cells are starved and then stimulated with 10% FBS in the presence of different concentrations of Triciribine. IC50 value of Triciribine is determined by detecting Phospho-Akt (Ser473) and phospho-p70S6K (Thr389) with western blotting. |
Cell Assay
[2]
|
Cell Lines |
OVCAR3, OVCAR8, PANC1, NIH3T3, PC-3, LNCaP, MDAMB-468, OVCAR5, DU-145, T47D, COLO357, LXSN-NIH3T3, WM35, and WM852 |
Concentrations |
Dissolved in DMSO, final concentrations ~20 μM |
Incubation Time |
24, and 48 hours |
Methods |
Cells are exposed to various concentrations of Triciribine for 24, and 48 hours. Cell survival is assayed with MTS. Apoptosis is detected with annexin V. |
Animal Study
[2]
|
Animal Models |
Female nude mice injected s.c. with OVCAR3, OVCAR8, PANC-1, OVCAR5, or COLO357 |
Formulation |
Dissolved in DMSO, and diluted in saline |
Doses |
1 mg/kg/day |
Administration |
Dosed i.p. |
References |
[1] Gürsel DB, et al. Neuro Oncol, 2011, 13(6), 610-621.
|
[2] Yang L, et al. Cancer Res, 2004, 64(13), 4394-4399.
|
[3] Lu CH, et al. Clin Cancer Res, 2007, 13(19), 5883-5888.
|
[4] Fernández de Mattos S, et al. Mol Cancer Ther, 2008, 7(10), 3237-3246.
|
[5] Dieterle A, et al. Int J Cancer, 2009, 125(4), 932-941.
|
[6] Berndt N, et al. Cell Death Differ, 2010, 17(11), 1795-1804.
|
|