Akt inhibitor induces apoptosis in human cancer cells

2560 Phosphoinositide 3-OH kinase (PI3-K) and its downstream target, Akt mediate one of the most important survival signaling pathways in cancer cells. The mechanism by which PI3-K/Akt pathway affects cell survival is through its downstream target proteins such as BAD, Caspase-9, Forkhead transcription factors, IKKα and TSC1/2. Therefore, inhibition of Akt activity is expected to induce apoptotic cell death at multiple levels. In addition, down-regulation of Akt signaling pathway may sensitize cancer cells to cytotoxic oncolytics. There are enormous clinical advantages in exploring this cell survival pathway. This makes Akt among the most validated and attractive targets for the discovery of efficacious therapeutics for the treatment of human cancers. Here we report that isoquinoline sulfonamide-based Akt kinase inhibitors exert potent anti-proliferative effect on U87MG human glioblastoma cells and Jurkat human T-cell leukemia cells. Both cell lines are PTEN-null with constitutively activated Akt. We further demonstrate that these AKT inhibitors induce a robust Caspases activation and rapid phosphatidyl serine (PS) exposure on cell surface, characteristic of cells undergoing rapid apoptosis. Data will also be presented to show that down-regulation of Akt activity either by Akt-specific siRNA or small molecule inhibitors sensitize cancer cells to various oncolytics such as Gemcitabine, Camptothecin and Dexamethasone, as well as TRAIL. We conclude that treatment of U87MG and Jurkat cells with isoquinoline sulfonamide class of Akt inhibitor results in apoptotic cell death. And these results support the notion that synergistic anticancer action can be achieved by combination therapy using Akt inhibitors and conventional cytotoxic cancer therapeutics.