Document Detail

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.
MedLine Citation:
PMID:  8260698     Owner:  NLM     Status:  MEDLINE    
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.
M Kizaki; Y Ikeda; R Tanosaki; H Nakajima; M Morikawa; A Sakashita; H P Koeffler
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Blood     Volume:  82     ISSN:  0006-4971     ISO Abbreviation:  Blood     Publication Date:  1993 Dec 
Date Detail:
Created Date:  1994-01-24     Completed Date:  1994-01-24     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  3592-9     Citation Subset:  AIM; IM    
Division of Hematology, Keio University School of Medicine, Tokyo, Japan.
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MeSH Terms
Cell Differentiation / drug effects*
Cell Division / drug effects*
Cell Line
DNA Probes
Dose-Response Relationship, Drug
Gene Expression / drug effects
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
Reg. No./Substance:
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

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