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.
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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)
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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
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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)
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