Inhibition of Akt/Survivin Pathway Synergizes the Antileukemia Effect of Nutlin-3 in Acute Lymphoblastic Leukemia Cells.

PI3k/Akt and p53 pathways are known to play anti- and pro-apoptotic roles in cell death, respectively. High level of PI3k/Akt activation by loss of PTEN expression and inactivation of p53 by overexpression of MDM2 are associated with cancer cell growth and progression. Here, we report that inhibition of PI3k/Akt either by PI3k inhibitor Ly294002 or by expression of PTEN synergizes the MDM2 antagonist nutlin-3 in inducing apoptosis in acute lymphoblastic leukemia (ALL). First, we tested the effect of nutlin-3 on induction of p53 and apoptosis in a set of ALL cell lines with wild-type (wt) p53 and MDM2 overexpression. The p53 was induced by nutlin-3 in all cell lines tested but induction of apoptosis was different in cells with distinct PTEN status. Nutlin-3 induced potent apoptosis in cell lines with PTEN expression but not in cell lines without PTEN expression. Consistent with the apoptotic effects, nutlin-3 significantly downregulated expression of survivin in PTEN-positive cells but not in PTEN-negative cells. When these nutlin-3 resistant cells were simultaneously treated with the PI3K inhibitor Ly294002 or pre-transfected with PTEN gene, their sensitivity to nutlin-3 was increased with a concomitant downregulation of survivin. Furthermore, direct silencing of survivin by siRNA increased the apoptotic effect of nutlin-3 on PTEN-negative ALL cells. Taken together, our results suggest that Akt-mediated survivin upregulation in PTEN-negative ALL cells attenuate nutlin-3 induced apoptosis, and combination of MDM2 antagonist and PI3K/Akt inhibitor may be a promising approach in the treatment of refractory ALL.