title: Combination treatment in vitro with Nutlin, a small-molecule antagonist of MDM2, and pegylated interferon-α 2a specifically targets JAK2V617F-positive polycythemia vera cells.
abstract: Interferon (IFN-α) is effective therapy for polycythemia vera (PV) patients, but it is frequently interrupted because of adverse events. To permit the long-term use of IFN, we propose combining low doses of IFN with Nutlin-3, an antagonist of MDM2, which is also capable of promoting PV CD34(+) cell apoptosis. Combination treatment with subtherapeutic doses of Peg IFN-α 2a and Nutlin-3 inhibited PV CD34(+) cell proliferation by 50% while inhibiting normal CD34(+) cells by 30%. Combination treatment with Nutlin-3 and Peg IFN-α 2a inhibited PV colony formation by 55%-90% while inhibiting normal colony formation by 22%-30%. The combination of these agents also decreased the proportion of JAK2V617F-positive hematopoietic progenitor cells in 6 PV patients studied. Treatment with low doses of Peg IFN-α 2a combined with Nutlin-3 increased phospho-p53 and p21 protein levels in PV CD34(+) cells and increased the degree of apoptosis. These 2 reagents affect the tumor suppressor p53 through different pathways with Peg IFN-α 2a activating p38 MAP kinase and STAT1, leading to increased p53 transcription, whereas Nutlin-3 prevents the degradation of p53. These data suggest that treatment with low doses of both Nutlin-3 combined with Peg IFN-α 2a can target PV hematopoietic progenitor cells, eliminating the numbers of malignant hematopoietic progenitor cells.
authors.affiliation: Division of Hematology/Oncology, Tisch Cancer Institute and Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Lu
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Wang
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Joseph
authors.initials: J
authors.lastname: Tripodi
authors.forename: Goar
authors.initials: G
authors.lastname: Mosoyan
authors.forename: John
authors.initials: J
authors.lastname: Mascarenhas
authors.forename: Marina
authors.initials: M
authors.lastname: Kremyanskaya
authors.forename: Vesna
authors.initials: V
authors.lastname: Najfeld
authors.forename: Ronald
authors.initials: R
authors.lastname: Hoffman
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D004359:Drug Therapy, Combination; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000473:pathology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D016898:Interferon-alpha / Q000494:pharmacology*; D053614:Janus Kinase 2 / Q000235:genetics*; D009154:Mutation / Q000187:drug effects* / Q000235:genetics; D010879:Piperazines / Q000494:pharmacology*; D011087:Polycythemia Vera / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011092:Polyethylene Glycols / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors*
chemical_list: D007093:Imidazoles; D016898:Interferon-alpha; D010879:Piperazines; D011994:Recombinant Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D011092:Polyethylene Glycols; C482205:nutlin 3; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C507924:JAK2 protein, human; D053614:Janus Kinase 2; C100416:peginterferon alfa-2a