MDM2 antagonist nutlin-3 is a potent inducer of apoptosis in pediatric acute lymphoblastic leukemia cells with wild-type p53 and overexpression of MDM2

Gu, Liqun; Zhu, Nianyong; Findley, Harry W.; Zhou, Mi

doi:10.1038/leu.2008.11

Cited by 100 publications

(113 citation statements)

References 40 publications

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“…42 This finding is in agreement with other studies showing the importance of survivin downregulation in nutlin-3a-induced cell death in pediatric acute lymphoblastic leukaemia. 20 In this study, we verified the significance of the p53 mutation functionally at codon-215 of exon-6, AGT [Ser]4TGT [Cys], identified here in DEL cells. Earlier studies, by using gene reporter assays, have shown that this p53 mutation retains residual transactivation activity, including the target proapoptotic genes Bax and Puma, although its significance remained unknown.…”

Section: Discussionmentioning

confidence: 68%

“…[10][11][12] Accordingly, in vitro and in vivo studies have shown that inhibition of Mdm2, a critical negative regulator of p53, by using a recently developed small molecule, nutlin-3a, results in reactivation of the p53 pathway and significant antitumour activity in a variety of solid tumours and some haematologic malignancies harbouring a wild-type (wt) p53 gene. [13][14][15][16][17][18][19][20][21][22][23][24][25] We have shown earlier that most ALK þ ALCL tumours express p53 protein at variable levels and carry a wt p53 gene. 26 In this study, we hypothesized that inhibition of the Mdm2-p53 interaction would result in reactivation of the p53 pathway in ALK þ ALCL cells.…”

Section: Introductionmentioning

confidence: 99%

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The therapeutic potential of p53 reactivation by nutlin-3a in ALK+ anaplastic large cell lymphoma with wild-type or mutated p53

et al. 2009

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p53 is expressed frequently, but is rarely mutated in anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) tumours. Nutlin-3a is a recently developed small molecule that targets Mdm2, a critical negative regulator of p53, and disrupts the p53-Mdm2 interaction resulting in p53 stabilization and activation. We show that nutlin-3a activates p53 in ALK þ ALCL cells carrying a wild type (wt) or mutated but partially functional p53 gene resulting in p53-dependent cell-cycle arrest and apoptosis. Cell-cycle arrest was associated with upregulation of the cyclin-dependent kinase inhibitor p21. Nutlin-3a-induced apoptotic cell death was accompanied by Bax and Puma upregulation, downregulation of Bcl-xl, survivin, and caspase-3 cleavage, and this was reduced when p53-dependent transactivation activity was inhibited by pifithrin-a, or when pifithrin-l was used to inhibit direct p53 targeting of mitochondria. Nutlin-3a sensitized the activation of the extrinsic apoptotic pathway in wt-p53 ALK þ ALCL cells, in part, through upregulation of DR-5 and downregulation of c-Flip S/L , and was synergistic with TRAIL in cell death induction. In addition, nutlin-3a treatment enhanced doxorubicin cytotoxicity against ALK þ ALCL cells harbouring mt p53, and this was associated with p73 upregulation. These data suggest that disruption of the p53-mdm2 interaction by nutlin-3a offers a novel therapeutic approach for ALK þ ALCL patients.

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Section: Discussionmentioning

confidence: 68%

Section: Introductionmentioning

confidence: 99%

The therapeutic potential of p53 reactivation by nutlin-3a in ALK+ anaplastic large cell lymphoma with wild-type or mutated p53

et al. 2009

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“…Another study showed that loss of p19 potentiated Nutlin‐3a‐induced growth inhibition of neuroblastoma cells 30. Further, MDM2 overexpression reportedly enhances cell sensitivity to Nutlin‐3a 31. We predict that the unique nature of each TP53 mutant ( e.g .…”

Section: Discussionmentioning

confidence: 80%

Nutlin‐3a selects for cells harbouring TP53 mutations

Kucab

Hollstein

Arlt

et al. 2016

Intl Journal of Cancer

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TP53 mutations occur in half of all human tumours. Mutagen‐induced or spontaneous TP53 mutagenesis can be studied in vitro using the human TP53 knock‐in (Hupki) mouse embryo fibroblast (HUF) immortalisation assay (HIMA). TP53 mutations arise in up to 30% of mutagen‐treated, immortalised HUFs; however, mutants are not identified until TP53 sequence analysis following immortalisation (2–5 months) and much effort is expended maintaining TP53‐WT cultures. In order to improve the selectivity of the HIMA for HUFs harbouring TP53 mutations, we explored the use of Nutlin‐3a, an MDM2 inhibitor that leads to stabilisation and activation of wild‐type (WT) p53. First, we treated previously established immortal HUF lines carrying WT or mutated TP53 with Nutlin‐3a to examine the effect on cell growth and p53 activation. Nutlin‐3a induced the p53 pathway in TP53‐WT HUFs and inhibited cell growth, whereas most TP53‐mutated HUFs were resistant to Nutlin‐3a. We then assessed whether Nutlin‐3a treatment could discriminate between TP53‐WT and TP53‐mutated cells during the HIMA (n = 72 cultures). As immortal clones emerged from senescent cultures, each was treated with 10 µM Nutlin‐3a for 5 days and observed for sensitivity or resistance. TP53 was subsequently sequenced from all immortalised clones. We found that all Nutlin‐3a‐resistant clones harboured TP53 mutations, which were diverse in position and functional impact, while all but one of the Nutlin‐3a‐sensitive clones were TP53‐WT. These data suggest that including a Nutlin‐3a counter‐screen significantly improves the specificity and efficiency of the HIMA, whereby TP53‐mutated clones are selected prior to sequencing and TP53‐WT clones can be discarded.

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“…Thus, p53 is potentially an important target in the treatment of drug-resistant leukemia. [44][45][46] Leukemic stem cells are frequently drug resistant. [47][48][49] Our results point out that one of the first events involved in this process is decreased expression of the p53 tumor suppressor protein.…”

Section: Discussionmentioning

confidence: 99%