| Effects of novel retinoic acid compound, 9-cis-retinoic acid, on proliferation, differentiation, and expression of retinoic acid receptor-alpha and retinoid X receptor-alpha RNA by HL-60 cells. | |
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MedLine Citation:
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PMID: 8260698 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Retinoic acid modulates proliferation and differentiation of a wide variety of normal and leukemic cells through two distinct families of transcriptional factors: the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). A stereoisomer of retinoic acid, 9-cis-retinoic acid, is a high-affinity ligand for RXR and binds efficiently to RAR. In contrast, all-trans-retinoic acid interacts 40-fold less efficiently with RXR as compared with RAR. To clarify the biologic role of retinoic acid compounds (all-trans,- 9-cis-, and 13-cis-retinoic acid) in hematopoietic cells, we studied their effects on clonal growth, differentiation, and expression of RAR-alpha and RXR-alpha genes in HL-60 cells. At very low concentrations (10(-15) to 10(-12) mmol/L), each retinoid enhanced clonal growth of HL-60 cells. These concentrations of the retinoids had no capacity to induce differentiation of leukemic cells as measured by ability either to reduce nitroblue tetrazolium and to express CD11b antigens, suggesting that retinoids at very low concentrations may stimulate proliferation of leukemic cells rather than induce their differentiation. These findings may help explain why patients with acute promyelocytic leukemia may relapse while receiving retinoic acids. With continuous therapy, retinoids are metabolized rapidly with increased urinary excretion, lowering their plasma levels to a range that may stimulate proliferation without inducing differentiation of leukemic cells. In contrast, we found that at higher concentrations (> or = 10(-11) mmol/L) each retinoid inhibited clonal growth, reduced c-myc RNA levels, and induced differentiation of HL-60 cells. 9-cis-retinoic acid was a slightly more potent inducer of differentiation than all-trans-retinoic acid; the mechanism for this increased potency and its clinical potential requires additional studies. Steady-state levels of RAR-alpha mRNA in HL-60 cells were not affected by either 9-cis- and all-trans-retinoic acid. In contrast, 9-cis-retinoic acid, but not all-trans-retinoic acid, reduced RXR-alpha mRNA accumulation in a dose-dependent manner. |
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Authors:
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M Kizaki; Y Ikeda; R Tanosaki; H Nakajima; M Morikawa; A Sakashita; H P Koeffler |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Blood Volume: 82 ISSN: 0006-4971 ISO Abbreviation: Blood Publication Date: 1993 Dec |
Date Detail:
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Created Date: 1994-01-24 Completed Date: 1994-01-24 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 7603509 Medline TA: Blood Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 3592-9 Citation Subset: AIM; IM |
Affiliation:
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Division of Hematology, Keio University School of Medicine, Tokyo, Japan. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Cell Differentiation
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drug effects* Cell Division / drug effects* Cell Line DNA Probes Dose-Response Relationship, Drug Gene Expression / drug effects Humans Leukemia, Promyelocytic, Acute RNA, Neoplasm / biosynthesis*, isolation & purification Receptors, Cytoplasmic and Nuclear / biosynthesis*, drug effects Receptors, Retinoic Acid / biosynthesis*, drug effects Retinoid X Receptors Retinoids / metabolism Structure-Activity Relationship Transcription Factors* Tretinoin / analogs & derivatives*, metabolism, pharmacology* Tumor Cells, Cultured |
| Grant Support | |
ID/Acronym/Agency:
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CA26038/CA/NCI NIH HHS; CA33936/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/DNA Probes; 0/RNA, Neoplasm; 0/Receptors, Cytoplasmic and Nuclear; 0/Receptors, Retinoic Acid; 0/Retinoid X Receptors; 0/Retinoids; 0/Transcription Factors; 302-79-4/Tretinoin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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