Deguelin, a naturally occurring rotenoid, is known to be an Akt inhibitor and to have an anti-tumor effect on several cancers; decrease levels of phosphorylated Akt.
IC50 Value:
Target: Akt; Anti-cancer
in vitro: Deguelin in a dose and time dependent manner inhibited the growth of MDA-MB-231, MDA-MB-468, BT-549 and BT-20 cells [1]. Deguelin administration causes a significant HNSCC cell death. Deguelin induces both cell apoptosis and autophagy by modulating multiple signaling pathways in cultured HNSCC cells. Deguelin inhibits Akt signaling, and down-regulates survivin and cyclin-dependent kinase 4 (Cdk4) expressions, by disrupting their association with heat shock protein-90 (Hsp-90). Deguelin induces ceramide production through de novo synthase pathway to promote HNSCC cell death. Importantly, increased ceramide level activates AMP-activated protein kinase (AMPK), which then directly phosphorylates Ulk1 and eventually leads to cell autophagy [2]. Deguelin inhibited the proliferation of MPC-11 cells in a concentration- and time-dependent manner and caused the apoptotic death of MPC-11 cells. Following exposure to deguelin, the phosphorylation of Akt was decreased. The inhibition of cell growth may be associated with decreased levels of phosphorylated Akt. Deguelin-induced apoptosis was characterized by the upregulation of Bax, downregulation of Bcl-2 and activation of caspase-3 [3].
in vivo: Deguelin (2 or 4 mg/kg body weight), when injected intraperitoneally, reduced the in vivo tumor growth of MDA-MB-231 cells transplanted subcutaneously in athymic mice. Moreover it was nontoxic as evident from daily observations on mobility, food and water consumption and comparison of bodyweight and other visceral organ weights with those in control animals at the termination of the study [1]. In the colon cancer xenograft model, the volume of the tumor treated withdeguelin was significantly lower than that of the control, and the apoptotic index for deguelin-treated mice was much higher [4].

3CAI

3CAI is a potent allosteric and specific AKT inhibitor, which exerts efficacy in vitro and in vivo.
IC50 value:
Target: Akt
in vitro: 3CAI (1 μM) suppressed only AKT1 kinase activity and the other kinases tested were not affected by 3CAI. 3CAI is a much more potent AKT1 inhibitor than PI3K (60% inhibition at 1 vs 10 μM, respectively). 3CAI, but not I3C, substantially suppressed AKT1 activity as well as AKT2 activity in a dose dependent manner [1]. The AKT-mediated phosphorlyation site of mTOR (Ser2448) and GSK3β (Ser9) were substantially decreased by 3CAI in a time-dependent manner. However, phosphorylation of AKT (Thr308) was not changed. Furthermore, pro-apoptotic marker proteins p53 and p21 were also upregulated by 3CAI after 12 or 24 h of treatment. Additionally, the anti-apoptotic marker protein Bcl2 and AKT-mediated phosphorylation of ASK1 (Ser83) were significantly decreased [1].
in vivo: Mice were orally administered 3CAI at 20 or 30 mg/kg, I3C at 100 mg/kg, or vehicle 5 times a week for 21 days. Treatment of mice with 30 mg/kg of 3CAI significantly suppressed HCT116 tumor growth by 50% relative to the vehicle-treated group. Remarkably, mice seemed to tolerate treatment with these doses of 3CAI without overt signs of toxicity or significant loss of body weight compared with vehicle-treated group. Expression of these AKT-target proteins was strongly suppressed by 30mg/kg of 3CAI in tumor tissues [1].