Abstract | OBJECTIVE: MATERIALS AND METHODS: The redox function of APE1 was studied using the small molecule inhibitor E3330 in HL-60 and PLB acute myeloid leukemia cells. Electrophoretic mobility shift assays were employed to determine effect of inhibitor on APE1/Ref-1 redox signaling function. Trypan blue assays, Annexin-V/ propidium iodide and CD11b staining, and real-time polymerase chain reaction analyses were employed to determine survival, apoptosis, and differentiation status of cells in culture. RESULTS: RARĪ± binds to its RARE in a redox-dependent manner mediated by APE1/Ref-1 redox regulation. Redox-dependent RAR-RARE binding is blocked by E3330, a small molecule redox inhibitor of APE1/Ref-1. Combination treatment of RA + E3330 results in a profound hypersensitivity of myeloid leukemia cells to RA-induced differentiation and apoptosis. Additionally, redox inhibition by E3330 results in enhanced RAR target gene, BLR-1, expression in myeloid leukemia cells. CONCLUSIONS: The redox function of APE1/Ref-1 regulates RAR binding to its DNA RAREs influencing the response of myeloid leukemia cells to RA-induced differentiation. Targeting of APE1/Ref-1 redox function may allow manipulation of the retinoid response with therapeutic implications.
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Authors | Melissa L Fishel, E Scott Colvin, Meihua Luo, Mark R Kelley, Kent A Robertson |
Journal | Experimental hematology
(Exp Hematol)
Vol. 38
Issue 12
Pg. 1178-88
(Dec 2010)
ISSN: 1873-2399 [Electronic] Netherlands |
PMID | 20826193
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2010 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved. |
Chemical References |
- Benzoquinones
- CXCR5 protein, human
- Propionates
- RARA protein, human
- Receptors, CXCR5
- Receptors, Retinoic Acid
- Retinoic Acid Receptor alpha
- E 3330
- Tretinoin
- APEX1 protein, human
- DNA-(Apurinic or Apyrimidinic Site) Lyase
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Topics |
- Apoptosis
(drug effects)
- Benzoquinones
(pharmacology)
- Cell Differentiation
(drug effects)
- Cell Line, Tumor
- Cell Proliferation
(drug effects)
- DNA-(Apurinic or Apyrimidinic Site) Lyase
(antagonists & inhibitors, physiology)
- Humans
- Leukemia, Myeloid
(drug therapy, pathology)
- Oxidation-Reduction
- Propionates
(pharmacology)
- Receptors, CXCR5
(analysis)
- Receptors, Retinoic Acid
(metabolism)
- Response Elements
- Retinoic Acid Receptor alpha
- Tretinoin
(pharmacology)
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