Triciribine is an inhibitor of DNA synthesis for Akt and HIV-1 with IC50 values of 130 nM and 20 nM, respectively. [1,2]
Protein kinase B (PKB), also known as Akt, is a serine/threonine-specific protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription and cell migration. Once PH domain of Akt bind phospholipids ,the activated Akt can then go on to activate or deactivate its myriad substrates via its kinase activity. e.g. Nuclear Factor-kB, Bcl-2 family proteins and murine double minute 2 (MDM2).[3] Studies show that tumor cells have constantly active Akt depending on Akt for survival [4], so Akt inhibitors may treat cancers.
Triciribine, also known as API-2, suppresses the phosphorylation level and kinase activity of Akt, result in induce apoptosis and cell growth in cancer cell. Triciribine can specifically inhibit the most common astrocytic tumor cells inhibitory efficiency was very low (13.6 mM [5] GI50). Triciribine can inhibit HIV-1, IC50 20 nM. The amount of inhibition of 0.1 M can produce >90% ratio, dosage of 5 M could completely inhibit coenocytic. In the same cell line cytotoxicity test results showed when the concentration of Triciribine for the selective index of 46 M to 2250 using HIV-1 infected CEM-SS, H9, and B and U1 persistent infection of H9III cells of p24 core antigen, Triciribine can significantly inhibit HIV-1 induced generation, reverse transcriptase and the generation of infectious virus, this inhibition is dose dependent characteristics [6]. Triciribine inhibits human prostate cancer cell line PC-3 in the Akt 308 bit acid and serine 473 phosphorylation and Akt activity. Triciribine make PC-3 cells more sensitive to apoptosis induced by TRAIL- and anti-CD95, but to DNA damage caused by chemotherapy is still resistance [7]. Triciribine also can selectively inhibit Akt1, Akt2, and Akt3 without inhibiting known upstream activators, PDK1 and PI3K, of Akt. Additionally, Triciribine has antineoplastic and antiviral activity at low micromolar and submicromolar concentrations, and has been demonstrated to inhibit incorporation of amino acids into proteins and purine nucleotide synthesis.
Reference:
1 Gursel DB, et al. “Control of proliferation in astrocytoma cells by the receptor tyrosine kinase/PI3K/AKT signaling axis and the use of PI-103 and TCN as potential anti-astrocytoma therapies”. Nero Oncol, 2011, 13(6), 610-621.
2 Kucera LS, et al, AIDS Res Hum Retroviruses, 1993, 9(4), 307-314.
3 Song G, Ouyang G, Bao S. "The activation of Akt/PKB signaling pathway and cell survival". J. Cell. Mol. Med, 2005, 9 (1): 59-71.
4 Lindhurst MJ, Sapp JC, Teer JK, Johnston JJ, Finn EM, Peters K et al. "A mosaic activating mutation in AKT1 associated with the Proteus syndrome". N. Engl. J. Med, 2011, 365 (7): 611-9.
5 Gursel DB, et al, Nero Oncol, 2011, 13(6), 610-621.
6 Dieterle A, et al, Int J Cancer , 2009, 125(4), 932-941.
7 Yang L, et al, Cancer Res, 2004, 64(13), 4394-4399.
| Cell experiment [1-3]: | |
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Cell lines |
Astrocytoma cells, HIV-1, PC-3 cells |
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Preparation method |
The solubility of this compound in DMSO is >118.4mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reacting condition |
IC50: 130 nM (Akt), IC50: 0.02-0.46 μM (HIV-1/2) |
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Applications |
Triciribine (1-10 μM) inhibited cell growth in Nf1 and Trp53 mutant astrocytoma cells. Triciribine (100 μM) inhibited phosphorylation of Akt and p70S6K to basal levels. Triciribine incompletely inhibited the WHO II K1861-10 line with a GI50 value of 1.7 μM. Triciribine inhibited tumor lines (KR158, KR130, and SF295) to a greater extent at lower GI50 values (0.4–1.1 μM). Triciribine inhibited HIV-1with an IC50 of 20 nM. Triciribine (5 μM) completely inhibited syncytia formation. Triciribine markedly inhibited HIV-1-induced p24 core antigen production, reverse transcriptase, and infectious virus production in a dose-dependent manner using HIV-1 acutely infected CEM-SS, H9, and persistently infected H9III B and U1 cells. Triciribine inhibited Akt phosphorylation at Thr308 and Ser473 and Akt activity in the human prostate cancer cell line PC-3. |
| Animal experiment [4]: | |
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Animal models |
Nude mice bearing OVCAR3, OVCAR8 and PANC1 tumor |
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Dosage form |
Intraperitoneal injection, 1 mg/kg/day, 7 days |
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Application |
Triciribin treatment inhibited OVCAR3, OVCAR8 and PANC1 tumor growth. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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参考文献: [1]. Gürsel D B, Connell-Albert Y S, Tuskan R G, et al. Control of proliferation in astrocytoma cells by the receptor tyrosine kinase/PI3K/AKT signaling axis and the use of PI-103 and TCN as potential anti-astrocytoma therapies[J]. Neuro-oncology, 2011, 13(6): 610-621. [2]. KUCERA L S, IYER N P, PUCKETT S H, et al. Activity of triciribine and triciribine-5′-monophosphate against human immunodeficiency virus types 1 and 2[J]. AIDS research and human retroviruses, 1993, 9(4): 307-314. [3]. Dieterle A, Orth R, Daubrawa M, et al. The Akt inhibitor triciribine sensitizes prostate carcinoma cells to TRAIL‐induced apoptosis[J]. International journal of cancer, 2009, 125(4): 932-941. [4]. Yang L, Dan H C, Sun M, et al. Akt/protein kinase B signaling inhibitor-2, a selective small molecule inhibitor of Akt signaling with antitumor activity in cancer cells overexpressing Akt[J]. Cancer research, 2004, 64(13): 4394-4399. |
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