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 language | English |
|---|---|
| Pages (from-to) | 853-861 |
| Number of pages | 9 |
| Journal | Neoplasia (United States) |
| Volume | 9 |
| Issue number | 10 |
| DOIs | |
| Publication status | Published - 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
The MDM-2 antagonist nutlin-3 promotes the maturation of acute myeloid leukemic blasts. / Secchiero, Paola; Zerbinati, Carlotta; Melloni, Elisabetta; Milani, Daniela; Campioni, Diana; Fadda, Roberto; Tiribelli, Mario; Zauli, Giorgio.
In: Neoplasia (United States), Vol. 9, No. 10, 10.2007, p. 853-861.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The MDM-2 antagonist nutlin-3 promotes the maturation of acute myeloid leukemic blasts
AU - Secchiero, Paola
AU - Zerbinati, Carlotta
AU - Melloni, Elisabetta
AU - Milani, Daniela
AU - Campioni, Diana
AU - Fadda, Roberto
AU - Tiribelli, Mario
AU - Zauli, Giorgio
PY - 2007/10
Y1 - 2007/10
N2 - 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.
AB - 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.
KW - Acute myeloid leukemia
KW - Apoptosis
KW - HL-60 cells
KW - p53 pathway
KW - Surface antigens
UR - http://www.scopus.com/inward/record.url?scp=35448932303&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=35448932303&partnerID=8YFLogxK
U2 - 10.1593/neo.07523
DO - 10.1593/neo.07523
M3 - Article
VL - 9
SP - 853
EP - 861
JO - Neoplasia
JF - Neoplasia
SN - 1522-8002
IS - 10
ER -