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: Min Lu, Xiaoli Wang, Yan Li, Joseph Tripodi, Goar Mosoyan, John Mascarenhas, Marina Kremyanskaya, Vesna Najfeld, Ronald Hoffman
• Journal: Blood (Blood) Vol. 120 Issue 15 Pg. 3098-105 (Oct 11 2012) ISSN: 1528-0020 [Electronic] United States
• PMID: 22872685 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Imidazoles
• Interferon-alpha
• Piperazines
• Recombinant Proteins
• TP53 protein, human
• Tumor Suppressor Protein p53
• Polyethylene Glycols
• nutlin 3
• MDM2 protein, human
• Proto-Oncogene Proteins c-mdm2
• JAK2 protein, human
• Janus Kinase 2
• peginterferon alfa-2a

Topics

• Apoptosis (drug effects)
• Blotting, Western
• Drug Therapy, Combination
• Hematopoietic Stem Cells (drug effects, pathology)
• Humans
• Imidazoles (pharmacology)
• In Vitro Techniques
• Interferon-alpha (pharmacology)
• Janus Kinase 2 (genetics)
• Mutation (drug effects, genetics)
• Piperazines (pharmacology)
• Polycythemia Vera (drug therapy, genetics, pathology)
• Polyethylene Glycols (pharmacology)
• Polymerase Chain Reaction
• Proto-Oncogene Proteins c-mdm2 (antagonists & inhibitors)
• Recombinant Proteins (pharmacology)
• Tumor Cells, Cultured
• Tumor Suppressor Protein p53 (antagonists & inhibitors)