TY - JOUR T1 - Dasatinib plus Nutlin-3 shows synergistic antileukemic activity in both p53 wild-type and p53 mutated B chronic lymphocytic leukemias by inhibiting the Akt pathway. JF - Clin Cancer Res Y1 - 2011 A1 - Zauli, Giorgio A1 - Voltan, Rebecca A1 - Bosco, Raffaella A1 - Melloni, Elisabetta A1 - Marmiroli, Sandra A1 - Rigolin, Gian Matteo A1 - Cuneo, Antonio A1 - Secchiero, Paola KW - Antineoplastic Agents KW - Apoptosis KW - Cell Line, Tumor KW - Cell Survival KW - Down-Regulation KW - Drug Synergism KW - Humans KW - Imidazoles KW - Leukemia, Lymphocytic, Chronic, B-Cell KW - Mutation KW - Piperazines KW - Protein Kinase Inhibitors KW - Protein Kinases KW - Proto-Oncogene Proteins c-akt KW - Pyrimidines KW - Thiazoles KW - Transcription, Genetic KW - Tumor Suppressor Protein p53 AB -

PURPOSE: To analyze the effect of the combination of Dasatinib, a multikinase inhibitor, plus Nutlin-3, a nongenotoxic activator of the p53 pathway, in primary B chronic lymphocytic leukemia (B-CLL) patient samples and B leukemic cell line models.

EXPERIMENTAL DESIGN: The induction of cytotoxicity was evaluated in both primary B-CLL cell samples (n = 20) and in p53(wild-type) (EHEB, JVM-2) and p53(deleted/mutated) (MEC-2, BJAB) B leukemic cell lines. The role of Akt in modulating leukemic cell survival/apoptosis in response to Dasatinib or Dasatinib + Nutlin-3 was documented by functional experiments carried out using specific pharmacological inhibitors and by overexpression of membrane-targeted constitutively active form of Akt.

RESULTS: The combination of Dasatinib + Nutlin-3 exhibited a synergistic cytotoxicity in the majority (19 out of 20) of B-CLL samples, including patients carrying 17p- (n = 4), and in both p53(wild-type) and p53(deleted/mutated) B leukemic cell lines. At the molecular level, Dasatinib significantly counteracted the Nutlin-3-mediated induction of the p53 transcriptional targets MDM2 and p21 observed in p53(wild-type) leukemic cells. Conversely, Nutlin-3 did not interfere with the ability of Dasatinib to decrease the phosphorylation levels of ERK1/2, p38/MAPK, and Akt in both p53(wild-type) and p53(deleted/mutated) B leukemic cell lines. A critical role of Akt downregulation in mediating the antileukemic activity of Dasatinib and Dasatinib + Nutlin-3 was demonstrated in experiments carried out by specifically modulating the Akt pathway.

CONCLUSIONS: These findings suggest that Dasatinib + Nutlin-3 might represent an innovative therapeutic combination for both p53(wild-type) and p53(deleted/mutated) B-CLL.

VL - 17 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21106726?dopt=Abstract ER -