Activation of the p53 pathway by the MDM2 inhibitor nutlin-3a overcomes BCL2 overexpression in a preclinical model of diffuse large B-cell lymphoma associated with t(14;18)(q32;q21)

E. Drakos, R. R. Singh, G. Z. Rassidakis, E. Schlette, J. Li, F. X. Claret, R. J. Ford, Francisco Vega, L. J. Medeiros

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

p53 is frequently wild type (wt) in diffuse large B-cell lymphoma (DLBCL) associated with t(14;18)(q32;q21) that overexpresses BCL2. Nutlin-3a is a small molecule that activates the p53 pathway by disrupting p53-MDM2 interaction. We show that nutlin-3a activates p53 in DLBCL cells associated with t(14;18)(q32;q21), BCL2 overexpression and wt p53, resulting in cell cycle arrest and apoptosis. Nutlin-3a treatment had similar effects on DLBCL cells of activated B-cell phenotype with wt p53. Cell cycle arrest was associated with upregulation of p21. Nutlin-3a-induced apoptosis was accompanied by BAX and PUMA upregulation, BCL-XL downregulation, serine-70 dephosphorylation of BCL2, direct binding of BCL2 by p53, caspase-9 upregulation and caspase-3 cleavage. Cell death was reduced when p53-dependent transactivation activity was inhibited by pifithrin-α (PFT-α), or PFT-μ inhibited direct p53 targeting of mitochondria. Nutlin-3a sensitized activation of the intrinsic apoptotic pathway by BCL2 inhibitors in t(14;18)-positive DLBCL cells with wt p53, and enhanced doxorubicin cytotoxicity against t(14;18)-positive DLBCL cells with wt or mutant p53, the latter in part via p73 upregulation. Nutlin-3a treatment in a xenograft animal lymphoma model inhibited growth of t(14;18)-positive DLBCL tumors, associated with increased apoptosis and decreased proliferation. These data suggest that disruption of the p53-MDM2 interaction by nutlin-3a offers a novel therapeutic approach for DLBCL associated with t(14;18)(q32;q21).

Original languageEnglish
Pages (from-to)856-867
Number of pages12
JournalLeukemia
Volume25
Issue number5
DOIs
StatePublished - May 1 2011
Externally publishedYes

Fingerprint

Lymphoma, Large B-Cell, Diffuse
Up-Regulation
Apoptosis
Cell Cycle Checkpoints
Caspase 9
nutlin 3
Heterografts
Caspase 3
Doxorubicin
Serine
Transcriptional Activation
Lymphoma
Mitochondria
B-Lymphocytes
Cell Death
Down-Regulation
Animal Models
Phenotype
Growth
Neoplasms

Keywords

  • BCL2
  • diffuse large B-cell lymphoma
  • MDM2
  • Nutlin
  • p53
  • t(14;18)(q32;q21)

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

Cite this

Activation of the p53 pathway by the MDM2 inhibitor nutlin-3a overcomes BCL2 overexpression in a preclinical model of diffuse large B-cell lymphoma associated with t(14;18)(q32;q21). / Drakos, E.; Singh, R. R.; Rassidakis, G. Z.; Schlette, E.; Li, J.; Claret, F. X.; Ford, R. J.; Vega, Francisco; Medeiros, L. J.

In: Leukemia, Vol. 25, No. 5, 01.05.2011, p. 856-867.

Research output: Contribution to journalArticle

Drakos, E. ; Singh, R. R. ; Rassidakis, G. Z. ; Schlette, E. ; Li, J. ; Claret, F. X. ; Ford, R. J. ; Vega, Francisco ; Medeiros, L. J. / Activation of the p53 pathway by the MDM2 inhibitor nutlin-3a overcomes BCL2 overexpression in a preclinical model of diffuse large B-cell lymphoma associated with t(14;18)(q32;q21). In: Leukemia. 2011 ; Vol. 25, No. 5. pp. 856-867.
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AU - Schlette, E.

AU - Li, J.

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