Abstract
Unlike its cytotoxicity in p53-functional cell lines, Nutlin-1, the small-molecule inhibitor of murine double minute (MDM2), significantly enhanced the differentiation-inducing activity of all-trans retinoic acid (ATRA) in HL60 and NB4 cells (p53-nonfunctional) but not in U937 cells (p53 wild-type). Moreover, we demonstrated that the synergistic differentiation-inducing activity of Nutlin-1 combined with ATRA appeared in a p53-independent manner. In the present study, we found that ATRA could selectively induce expression of p-glycoprotein (p-gp) in HL60 and NB4 cells but not in U937 cells. Investigation of p-gp-ATPase activity showed that Nutlin-1 and ATRA were likely to act as p-gp transport substrates. Furthermore, Nutlin-1 enhanced the ability of ATRA to induce expression of the myeloid differentiation-related transcription factor C/EBPβ and to reduce expression of c-myc. Additionally, the expression of retinoic acid receptor α (RARα) was further reduced in cells treated with ATRA in combination with Nutlin-1. Taken together, the mechanisms of synergistic differentiation-inducing activity of Nutlin-1 combined with ATRA could be attributed to Nutlin-1 competitive binding to p-gp, leading to ATRA efflux inhibition, and then the differentiation pathways involved were therefore further activated. Nutlin-1 might be a useful adjuvant with ATRA for patients with retinoid-resistant leukemia induced by overexpression of p-gp.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Binding, Competitive
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Biological Transport
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CCAAT-Enhancer-Binding Protein-beta / metabolism
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Cell Differentiation / drug effects*
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Cell Proliferation / drug effects*
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Dose-Response Relationship, Drug
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Drug Synergism
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HL-60 Cells
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Humans
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Imidazoles / metabolism
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Imidazoles / pharmacology
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Leukemia, Myeloid / genetics
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Leukemia, Myeloid / metabolism*
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Leukemia, Myeloid / pathology
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Piperazines / metabolism
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Piperazines / pharmacology
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Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors
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Proto-Oncogene Proteins c-mdm2 / metabolism
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Proto-Oncogene Proteins c-myc / metabolism
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RNA Interference
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Receptors, Retinoic Acid / metabolism
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Retinoic Acid Receptor alpha
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Time Factors
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Transfection
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Tretinoin / metabolism
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Tretinoin / pharmacology
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism
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U937 Cells
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Verapamil / pharmacology
Substances
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ABCB1 protein, human
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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CCAAT-Enhancer-Binding Protein-beta
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CEBPB protein, human
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Imidazoles
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MYC protein, human
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Piperazines
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Proto-Oncogene Proteins c-myc
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RARA protein, human
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Receptors, Retinoic Acid
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Retinoic Acid Receptor alpha
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TP53 protein, human
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Tumor Suppressor Protein p53
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nutlin 1
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Tretinoin
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Verapamil
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2