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
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Stefania Trino1, Ilaria Iacobucci2, Daniela Erriquez3, Ilaria Laurenzana1, Luciana De Luca1, Anna Ferrari2, Andrea Ghelli Luserna Di Rorà2, Cristina Papayannidis2, Enrico Derenzini2, Giorgia Simonetti2, Annalisa Lonetti4, Claudia Venturi2, Federica Cattina5, Emanuela Ottaviani2, Maria Chiara Abbenante2, Domenico Russo5, Giovanni Perini3, Pellegrino Musto6, Giovanni Martinelli2
1Laboratory of Pre-Clinical and Translational Research, IRCCS Referral Cancer Center of Basilicata, Rionero in Vulture (PZ), Italy
2Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology “L. and A. Seràgnoli”, University of Bologna, Bologna, Italy
3Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
4Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
5Chair of Hematology and BMT Unit, University of Brescia, Brescia, Italy
6Scientific Direction, IRCCS Referral Cancer Center of Basilicata, Rionero in Vulture (PZ), Italy
Stefania Trino, e-mail: [email protected]
Giovanni Martinelli, e-mail: [email protected]
Keywords: acute lymphoblastic leukemia, p53, MDM2, Nutlin-3a
Received: June 09, 2015 Accepted: January 22, 2016 Published: February 12, 2016
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.
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