The MDM-2 antagonist nutlin-3 promotes the maturation of acute myeloid leukemic blasts

Paola Secchiero, Carlotta Zerbinati, Elisabetta Melloni, Daniela Milani, Diana Campioni, Roberto Fadda, Mario Tiribelli, Giorgio Zauli

Research output: Contribution to journalArticle

Abstract

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) α, potentiated the maturational activity of recombinant TNF-related apoptosis-inducing ligand (TRAIL) in HL-60 cells. However, although TNF-α 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.

Original languageEnglish
Pages (from-to)853-861
Number of pages9
JournalNeoplasia (United States)
Volume9
Issue number10
DOIs
Publication statusPublished - Oct 2007

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Keywords

  • Acute myeloid leukemia
  • Apoptosis
  • HL-60 cells
  • p53 pathway
  • Surface antigens

ASJC Scopus subject areas

  • Cancer Research

Cite this

Secchiero, P., Zerbinati, C., Melloni, E., Milani, D., Campioni, D., Fadda, R., Tiribelli, M., & Zauli, G. (2007). The MDM-2 antagonist nutlin-3 promotes the maturation of acute myeloid leukemic blasts. Neoplasia (United States), 9(10), 853-861. https://doi.org/10.1593/neo.07523