The MDM-2 antagonist nutlin-3 promotes the maturation of acute myeloid leukemic blasts.
The small-molecule inhibitor of murine double minute (MDM-2), Nutlin-3, induced variable apoptosis in primary acute myeloid leukemia (AML) blasts and promoted myeloid maturation of surviving cells, as demonstrated by analysis of CD11b and CD14 surface antigens and by morphologic examination. Although the best-characterized activity of Nutlin-3 is activation of the p53 pathway, Nutlin-3 induced maturation also in one AML sample characterized by p53 deletion, as well as in the p53(-/-) human myeloblastic HL-60 cell line. At the molecular level, the maturational activity of Nutlin-3 in HL-60 cells was accompanied by the induction of E2F1 transcription factor, and it was significantly counteracted by specific gene knockdown with small interfering RNA for E2F1. Moreover, Nutlin-3, as well as tumor necrosis factor (TNF) alpha, potentiated the maturational activity of recombinant TNF-related apoptosis-inducing ligand (TRAIL) in HL-60 cells. However, although TNF-alpha significantly counteracted the proapoptotic activity of TRAIL, Nutlin-3 did not interfere with the proapoptotic activity of TRAIL. Taken together, these data disclose a novel, potentially relevant therapeutic role for Nutlin-3 in the treatment of both p53 wild-type and p53(-/-) AML, possibly in association with recombinant TRAIL.
Secchiero
Paola
P
Department of Morphology and Embryology, University of Ferrara, Ferrara, Italy. sccpla@unife.it
Zerbinati
Carlotta
C
Melloni
Elisabetta
E
Milani
Daniela
D
Campioni
Diana
D
Fadda
Roberto
R
Tiribelli
Mario
M
Zauli
Giorgio
G
D000208:Acute Disease; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D039481:CD11b Antigen / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D050687:E2F1 Transcription Factor / Q000187:drug effects / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D047468:Immunoprecipitation; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000187:drug effects / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein / Q000096:biosynthesis / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000187:drug effects / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000378:metabolism
D000970:Antineoplastic Agents; D039481:CD11b Antigen; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D007093:Imidazoles; D018950:Lipopolysaccharide Receptors; D010879:Piperazines; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; D051736:Proto-Oncogene Proteins c-mdm2