The therapeutic potential of p53 reactivation by nutlin-3a in ALK+ anaplastic large cell lymphoma with wild-type or mutated p53.
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+ 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-alpha, or when pifithrin-mu was used to inhibit direct p53 targeting of mitochondria. Nutlin-3a sensitized the activation of the extrinsic apoptotic pathway in wt-p53 ALK+ 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+ 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+ ALCL patients.
Drakos
E
E
Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Atsaves
V
V
Schlette
E
E
Li
J
J
Papanastasi
I
I
Rassidakis
G Z
GZ
Medeiros
L J
LJ
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D004357:Drug Synergism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D017728:Lymphoma, Large-Cell, Anaplastic / Q000188:drug therapy* / Q000235:genetics; D009154:Mutation; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D007093:Imidazoles; D010879:Piperazines; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; D004317:Doxorubicin