title: Targeting the p53-MDM2 interaction by the small-molecule MDM2 antagonist Nutlin-3a: a new challenged target therapy in adult Philadelphia positive acute lymphoblastic leukemia patients.
abstract: MDM2 is an important negative regulator of p53 tumor suppressor. In this study, we sought to investigate the preclinical activity of the MDM2 antagonist, Nutlin-3a, in Philadelphia positive (Ph+) and negative (Ph-) leukemic cell line models, and primary B-acute lymphoblastic leukemia (ALL) patient samples. We demonstrated that Nutlin-3a treatment reduced viability and induced p53-mediated apoptosis in ALL cells with wild-type p53 protein, in a time and dose-dependent manner, resulting in the increased expression of pro-apoptotic proteins and key regulators of cell cycle arrest. The dose-dependent reduction in cell viability was confirmed in primary blast cells from B-ALL patients, including Ph+ ALL resistant patients carrying the T315I BCR-ABL1 mutation. Our findings provide a strong rational for further clinical investigation of Nutlin-3a in Ph+ and Ph- ALL.
authors.affiliation: Laboratory of Pre-Clinical and Translational Research, IRCCS Referral Cancer Center of Basilicata, Rionero in Vulture, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Trino
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. and A. Seràgnoli", University of Bologna, Bologna, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Iacobucci
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Erriquez
authors.affiliation: Laboratory of Pre-Clinical and Translational Research, IRCCS Referral Cancer Center of Basilicata, Rionero in Vulture, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Laurenzana
authors.affiliation: Laboratory of Pre-Clinical and Translational Research, IRCCS Referral Cancer Center of Basilicata, Rionero in Vulture, Italy.
authors.forename: Luciana
authors.initials: L
authors.lastname: De Luca
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. and A. Seràgnoli", University of Bologna, Bologna, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Ferrari
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. and A. Seràgnoli", University of Bologna, Bologna, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ghelli Luserna Di Rorà
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. and A. Seràgnoli", University of Bologna, Bologna, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Papayannidis
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. and A. Seràgnoli", University of Bologna, Bologna, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Derenzini
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. and A. Seràgnoli", University of Bologna, Bologna, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Simonetti
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Lonetti
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. and A. Seràgnoli", University of Bologna, Bologna, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Venturi
authors.affiliation: Chair of Hematology and BMT Unit, University of Brescia, Brescia, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Cattina
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. and A. Seràgnoli", University of Bologna, Bologna, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Ottaviani
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. and A. Seràgnoli", University of Bologna, Bologna, Italy.
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Abbenante
authors.affiliation: Chair of Hematology and BMT Unit, University of Brescia, Brescia, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Russo
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Perini
authors.affiliation: Scientific Direction, IRCCS Referral Cancer Center of Basilicata, Rionero in Vulture, Italy.
authors.forename: Pellegrino
authors.initials: P
authors.lastname: Musto
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. and A. Seràgnoli", University of Bologna, Bologna, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Martinelli
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000494:pharmacology*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D010879:Piperazines; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: MDM2; Nutlin-3a; acute lymphoblastic leukemia; p53