MDM2 Antagonists Activate p53 and Synergize with Genotoxic Drugs To Induce Apoptosis in B-Cell Chronic Lymphocytic Leukemia Cells but Not in T Cells.

B-cell chronic lymphocytic leukemia (B-CLL) is characterized by the accumulation of long-lived CD5+ B lymphocytes. Several drugs used currently in the therapy of B-CLL act, at least partially, through activation of the p53 pathway. Recently, non-genotoxic small-molecule activators of p53, the nutlins, have been identified that inhibit p53-MDM2 binding. We have investigated the antitumor potential of nutlin-3 in B-CLL and find that it can effectively activate the p53 pathway and induce apoptosis in cells with wild-type but not mutant p53. The half-maximal effective concentration (EC50) for B-CLL cells was 4.7 ± 1.5 μM (n = 8). Nutlin-3 stabilized p53 and induced several p53 target genes including MDM2, p21, PUMA, Bax, PIG3 and WIG1. At lower concentrations, nutlin-3 synergized with the genotoxic drugs doxorubicin, chlorambucil, and fludarabine but not with acadesine, that induces p53-independent apoptosis. Normal human T cells showed lower sensitivity to nutlin-3 than B-CLL cells and no synergism with the genotoxic drugs. These results suggest that MDM2 antagonists alone or in combination with chemotherapeutic drugs may offer a new treatment option for B-CLL.