Akt can suppress apoptosis by directly interacting with and phosphorylating these proapoptotic proteins. This cascade is thus an exciting new target for molecular targeting therapy for cancer. Our results show that LY294002 markedly inhibited NPC CNE 2Z cell growth, proliferation, and induced apoptosis in vitro and in vivo. Previous studies have demonstrated that the expression of phosphorylated Akt had a closely correlated to cell growth, proliferation, and resistance to apoptosis. In addition, LY294002, the PI3K/Akt spe cific inhibitor, showed the growth inhibitory effects due to cell cycle arrest closely correlated to with the accumu lation of cyclin dependent kinase inhibitors p27 and PTEN. Some studies found that PI3K inhibi tors produce apoptosis and antiproliferative effects on pancreatic carcinoma cells in vivo and in vitro.

To evaluate the role of Akt in the biology of NPC, we used immunoblotting to analyse the relationship between phosphorylation specific antibody to demonstrate Akt activity in cultured cells and then confirmed the ability of the LY294002 to decrease Akt phosphorylation in NPC cell line and xenograft tumor tissue. We examined the effect of LY294002 on cell proliferation and the induction of apoptosis. However, there was a great discrepancy between the sensitivity to LY294002 and the level of expression of phosphorylated Akt. The degree of CNE 2Z cell proliferation and apoptosis was shown in a dose dependent fashion.Western blot results revealed decreasing of phosphorylated Akt levels with increasing dose of LY294002.

In tumor sections from athmic mice, the necrotic region treated with a higher dose LY294002 was more great than those of the lower dose of LY294002 and the control group. The mean body weight did not exhibit sig nificant Brefeldin_A differences between the groups treated with LY294002 and control group. However, compared with LY294002 and control group, the mean tumor burden was remarkably decreased in treated with LY294002 group, with signifi cant difference. Because the PI3K/Akt signaling pathway plays an important role in many aspects of cellular homeostasis, it is necessary concern that PI3K inhibitor would interfere with the survival and proliferation of critical populations of normal cells and show unacceptable toxic ity. Previous experiments have testified that it was safe biweekly i. p.

administration of under to 100 mg/kg of LY294002. The dose of LY294002 produced obvious inhibition of Akt phospho rylation, reduced tumor cell proliferation, and increased apoptosis in orthotopic CNE 2Z NPC xenografts. Akt specific inhibitor, LY294002, did not cause obvious apoptosis at 24 h exposure, but induced greatly apoptosis in 48 h in a time dependent manner. Some studies have clearly shown that Akt phosphorylates and inactivates cspase 9, an important initiation caspase of the mito chondria pathway mediated apoptosis.