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. Clin Cancer Res; 17(4); 1-9. ©2010 AACR.

Dasatinib Plus Nutlin-3 Shows Synergistic Antileukemic Activity inBoth p53wild-type and p53mutated B Chronic Lymphocytic Leukemias by Inhibitingthe Akt Pathway / Zauli, G; Voltan, R; Bosco, Raffaella; Melloni, E; Marmiroli, Sandra; Rigolin, Gm; Cuneo, A; Secchiero, P.. - In: CLINICAL CANCER RESEARCH. - ISSN 1078-0432. - STAMPA. - 17:(2011), pp. 762-770. [10.1158/1078-0432.CCR-10-2572]

Dasatinib Plus Nutlin-3 Shows Synergistic Antileukemic Activity inBoth p53wild-type and p53mutated B Chronic Lymphocytic Leukemias by Inhibitingthe Akt Pathway

BOSCO, Raffaella;MARMIROLI, Sandra;
2011

Abstract

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. Clin Cancer Res; 17(4); 1-9. ©2010 AACR.
2011
17
762
770
Dasatinib Plus Nutlin-3 Shows Synergistic Antileukemic Activity inBoth p53wild-type and p53mutated B Chronic Lymphocytic Leukemias by Inhibitingthe Akt Pathway / Zauli, G; Voltan, R; Bosco, Raffaella; Melloni, E; Marmiroli, Sandra; Rigolin, Gm; Cuneo, A; Secchiero, P.. - In: CLINICAL CANCER RESEARCH. - ISSN 1078-0432. - STAMPA. - 17:(2011), pp. 762-770. [10.1158/1078-0432.CCR-10-2572]
Zauli, G; Voltan, R; Bosco, Raffaella; Melloni, E; Marmiroli, Sandra; Rigolin, Gm; Cuneo, A; Secchiero, P.
File in questo prodotto:
File Dimensione Formato  
Dasatinib-plus-nutlin-3-shows-synergistic-antileukemic-activity-in-both-p53-wild-typeand-p53-mutated-B-chronic-lymphocytic-leukemias-by-inhibiting-the-Akt-pathway_2011_Clinical-Cancer-Research.pdf

Accesso riservato

Tipologia: Versione pubblicata dall'editore
Dimensione 749.32 kB
Formato Adobe PDF
749.32 kB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

Licenza Creative Commons
I metadati presenti in IRIS UNIMORE sono rilasciati con licenza Creative Commons CC0 1.0 Universal, mentre i file delle pubblicazioni sono rilasciati con licenza Attribuzione 4.0 Internazionale (CC BY 4.0), salvo diversa indicazione.
In caso di violazione di copyright, contattare Supporto Iris

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/648446
Citazioni
  • ???jsp.display-item.citation.pmc??? 28
  • Scopus 45
  • ???jsp.display-item.citation.isi??? 42
social impact