PMID- 10068679
OWN - NLM
STAT- MEDLINE
DCOM- 19990330
LR  - 20210216
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 93
IP  - 6
DP  - 1999 Mar 15
TI  - Effects of novel RAR- and RXR-selective retinoids on myeloid leukemic 
      proliferation and differentiation in vitro.
PG  - 2057-66
AB  - Retinoids such as all-trans-retinoic acid (ATRA) and 9-cis-retinoic acid 
      (9-cis-RA) have an important role in many aspects of proliferation and 
      differentiation of hematopoietic cells. They exert their effects by binding to 
      retinoic acid receptors (RARs) and/or retinoid X receptors (RXRs). We studied the 
      effects of novel retinoids on proliferation and differentiation of HL-60 and NB4 
      myeloid leukemic cells, as well as acute promyelocytic leukemia (APL) cells from 
      patients. RXR-selective SR11345 (Retinoid C) had little ability to inhibit the 
      clonal growth and to induce the differentiation of either HL-60 or NB4 cells. 
      However, SR11276 (Retinoid E), which activated both the RAR and RXR classes, and 
      SR11278 (Retinoid D), which activated the RAR subtypes alpha, beta, and gamma, 
      could inhibit clonal growth of both cell types, as well as leukemic cells from 
      APL patients. The combination of ATRA and either SR11276 or SR11278 additively 
      inhibited APL cell proliferation. SR11302 (Retinoid A), with reported anti-AP-1 
      activity and no activation of RARs and RXR and SR11363 (Retinoid B), which 
      selectively activated RARbeta and gamma, were inactive. The clonal proliferation 
      of both HL-60 and NB4 cells that were pulse-exposed to 10(-9) mol/L ATRA, 
      SR11276, SR11278, or SR11345 for 3 days, washed, and plated in methylcellulose 
      culture were inhibited by 0%, 51%, 21%, and 1% for HL-60 cells and 43%, 41%, 35%, 
      and 1% for NB4, respectively, compared with nontreated control cells. When the 
      HL-60 cells were pulse-exposed to 10(-9) mol/L of either SR11278 or SR11276, plus 
      10(-9) mol/L ATRA for 3 days, colony numbers were reduced by 46% and 64%, 
      respectively. Induction of leukemic cell differentiation as determined by the 
      nitroblue tetrazolium (NBT) assay showed that the combination of 10(-7) mol/L of 
      either SR11278 or SR11276 with 10(-7) mol/L ATRA had additive effects on HL-60 
      cells, NB4 cells, and fresh APL cells. Induction of CD11b expression on both 
      HL-60 and NB4 cells occurs during their differentiation. Expression of this 
      antigen was synergistically augmented by the combination of either 10(-7) to 
      10(-8) mol/L SR11278 or 10(-7) to 10(-9) mol/L SR11276 with 10(-9) mol/L ATRA 
      compared with either analog alone in HL-60 cells. Expression of the novel myeloid 
      specific transcription factor C/EBPepsilon was increased by SR11278 and SR11276 
      in both the HL-60 and NB4 cell lines. We conclude that retinoids or combination 
      of retinoids with specificities for both RAR and RXR may markedly enhance the 
      ability of ATRA to inhibit clonal growth and induce differentiation of HL-60 and 
      NB4 leukemic cells. This occurs in the absence of continuous contact with 
      retinoids.
FAU - Shiohara, M
AU  - Shiohara M
AD  - Department of Pediatrics, Shinshu University School of Medicine, Matsumoto Japan.
FAU - Dawson, M I
AU  - Dawson MI
FAU - Hobbs, P D
AU  - Hobbs PD
FAU - Sawai, N
AU  - Sawai N
FAU - Higuchi, T
AU  - Higuchi T
FAU - Koike, K
AU  - Koike K
FAU - Komiyama, A
AU  - Komiyama A
FAU - Koeffler, H P
AU  - Koeffler HP
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (CCAAT-Enhancer-Binding Proteins)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Receptors, Retinoic Acid)
RN  - 0 (Retinoid X Receptors)
RN  - 0 (Retinoids)
RN  - 0 (Transcription Factors)
RN  - 5688UTC01R (Tretinoin)
SB  - IM
MH  - CCAAT-Enhancer-Binding Proteins
MH  - Cell Differentiation/*drug effects
MH  - Cell Division/*drug effects
MH  - DNA-Binding Proteins/genetics
MH  - Dimerization
MH  - Gene Expression
MH  - Genes, Reporter
MH  - HL-60 Cells
MH  - Humans
MH  - Leukemia, Myeloid/*pathology
MH  - Nuclear Proteins/genetics
MH  - Receptors, Retinoic Acid/drug effects/genetics/*physiology
MH  - Retinoid X Receptors
MH  - Retinoids/*pharmacology
MH  - Transcription Factors/drug effects/genetics/*physiology
MH  - Transcriptional Activation/drug effects
MH  - Tretinoin/pharmacology
MH  - Tumor Cells, Cultured
EDAT- 1999/03/09 00:00
MHDA- 1999/03/09 00:01
CRDT- 1999/03/09 00:00
PHST- 1999/03/09 00:00 [pubmed]
PHST- 1999/03/09 00:01 [medline]
PHST- 1999/03/09 00:00 [entrez]
AID - S0006-4971(20)48681-1 [pii]
PST - ppublish
SO  - Blood. 1999 Mar 15;93(6):2057-66.