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      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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          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.

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          Most cited references 44

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          In vivo activation of the p53 pathway by small-molecule antagonists of MDM2.

          MDM2 binds the p53 tumor suppressor protein with high affinity and negatively modulates its transcriptional activity and stability. Overexpression of MDM2, found in many human tumors, effectively impairs p53 function. Inhibition of MDM2-p53 interaction can stabilize p53 and may offer a novel strategy for cancer therapy. Here, we identify potent and selective small-molecule antagonists of MDM2 and confirm their mode of action through the crystal structures of complexes. These compounds bind MDM2 in the p53-binding pocket and activate the p53 pathway in cancer cells, leading to cell cycle arrest, apoptosis, and growth inhibition of human tumor xenografts in nude mice.
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            p53 in health and disease.

            As a component of the response to acute stress, p53 has a well established role in protecting against cancer development. However, it is now becoming clear that p53 can have a much broader role and can contribute to the development, life expectancy and overall fitness of an organism. Although the function of p53 as a tumour suppressor ensures that we can't live without it, an integrated view of p53 suggests that not all of its functions are conducive to a long and healthy life.
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              Acute lymphoblastic leukaemia.

              Acute lymphoblastic leukaemia, a malignant disorder of lymphoid progenitor cells, affects both children and adults, with peak prevalence between the ages of 2 and 5 years. Steady progress in development of effective treatments has led to a cure rate of more than 80% in children, creating opportunities for innovative approaches that would preserve past gains in leukaemia-free survival while reducing the toxic side-effects of current intensive regimens. Advances in our understanding of the pathobiology of acute lymphoblastic leukaemia, fuelled by emerging molecular technologies, suggest that drugs specifically targeting the genetic defects of leukaemic cells could revolutionise management of this disease. Meanwhile, studies are underway to ascertain the precise events that take place in the genesis of acute lymphoblastic leukaemia, to enhance the clinical application of known risk factors and antileukaemic agents, and to identify treatment regimens that might boost the generally low cure rates in adults and subgroups of children with high-risk leukaemia.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                15 March 2016
                12 February 2016
                : 7
                : 11
                : 12951-12961
                Affiliations
                1 Laboratory of Pre-Clinical and Translational Research, IRCCS Referral Cancer Center of Basilicata, Rionero in Vulture (PZ), Italy
                2 Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology “L. and A. Seràgnoli”, University of Bologna, Bologna, Italy
                3 Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
                4 Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
                5 Chair of Hematology and BMT Unit, University of Brescia, Brescia, Italy
                6 Scientific Direction, IRCCS Referral Cancer Center of Basilicata, Rionero in Vulture (PZ), Italy
                Author notes
                Correspondence to: Stefania Trino, stefania.trino@ 123456crob.it
                Giovanni Martinelli, martg@ 123456tin.it
                Article
                7339
                10.18632/oncotarget.7339
                4914334
                26887044
                Copyright: © 2016 Trino et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Categories
                Research Paper

                Oncology & Radiotherapy

                p53, nutlin-3a, acute lymphoblastic leukemia, mdm2

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