PMID- 8634447
OWN - NLM
STAT- MEDLINE
DCOM- 19960710
LR  - 20210216
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 87
IP  - 5
DP  - 1996 Mar 1
TI  - Effects of novel retinoid X receptor-selective ligands on myeloid leukemia 
      differentiation and proliferation in vitro.
PG  - 1977-84
AB  - The biologic effects of retinoids such as all-trans-retinoic acid (ATRA) and 
      9-cis-retinoic acid on proliferation and differentiation of hematopoietic cells 
      are mediated by binding and activating two distinct families of transcription 
      factors: the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). 
      The RARs require heterodimerization with RXRs; in addition, RXRs can form 
      homodimers, which can bind to DNA response elements that are either distinct or 
      the same as those bound by the RAR/RXR heterodimers. Therefore, the two retinoid 
      pathways provide sequences that are specific for effective DNA binding and 
      activation of target genes. We have developed several series of novel synthetic 
      retinoids that selectively interact with RXR/RXR homodimers and RAR/RXR 
      heterodimers. We show here that SR11236 and SR11246, which are RXR-selective 
      analogs, had little ability to inhibit clonal growth and induce differentiation 
      of leukemic cells (HL-60 cells and fresh acute myeloid leukemia cells). However, 
      SR11249, SR11256, and LGD1069, which activated both RXR/RXR homodimers and 
      RAR/RXR heterodimers, could inhibit clonal growth and induce differentiation of 
      HL-60 cells as well as leukemic cells from patients, including those with acute 
      promyelocytic leukemia (APL). This is similar to results observed with 
      RAR/RXR-specific ligands. Interestingly, the combination of ATRA and either 
      SR11249, SR11256, or LGD1069 showed synergistic effects in inducing 
      differentiation of HL-60 cells. A retinoid (SR11238) with strong anti-AP-1 
      activity that did not activate the RARs and RXRs for gene transcription from the 
      response element TREpal was inactive in our assay systems, suggesting that the 
      antiproliferative effects of retinoids on leukemic cells is not mediated by 
      inhibiting the AP-1 pathway. We conclude that the RAR/RXR pathway is more 
      important than RXR/RXR pathway for differentiation and proliferation of acute 
      myeloid leukemic cells, and certain retinoids or combination of retinoids with 
      both RAR and RXR specificities may synergistically enhance the differentiation 
      activity of ATRA, which may be relevant in several clinical situations.
FAU - Kizaki, M
AU  - Kizaki M
AD  - Division of Hematology, Keio University School of Medicine, Tokyo, Japan.
FAU - Dawson, M I
AU  - Dawson MI
FAU - Heyman, R
AU  - Heyman R
FAU - Elster, E
AU  - Elster E
FAU - Morosetti, R
AU  - Morosetti R
FAU - Pakkala, S
AU  - Pakkala S
FAU - Chen, D L
AU  - Chen DL
FAU - Ueno, H
AU  - Ueno H
FAU - Chao, W
AU  - Chao W
FAU - Morikawa, M
AU  - Morikawa M
FAU - Ikeda, Y
AU  - Ikeda Y
FAU - Heber, D
AU  - Heber D
FAU - Pfahl, M
AU  - Pfahl M
FAU - Koeffler, H P
AU  - Koeffler HP
LA  - eng
GR  - CA33936/CA/NCI NIH HHS/United States
GR  - CA42710/CA/NCI NIH HHS/United States
GR  - DK42792/DK/NIDDK NIH HHS/United States
GR  - etc.
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Biomarkers)
RN  - 0 (Ligands)
RN  - 0 (Macrophage-1 Antigen)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (RARA protein, human)
RN  - 0 (Receptors, Retinoic Acid)
RN  - 0 (Retinoic Acid Receptor alpha)
RN  - 0 (Retinoid X Receptors)
RN  - 0 (Retinoids)
RN  - 0 (Tetrahydronaphthalenes)
RN  - 0 (Transcription Factor AP-1)
RN  - 0 (Transcription Factors)
RN  - 5688UTC01R (Tretinoin)
RN  - A61RXM4375 (Bexarotene)
SB  - IM
MH  - Bexarotene
MH  - Biomarkers
MH  - Cell Differentiation/drug effects
MH  - Cell Division/drug effects
MH  - Drug Synergism
MH  - Gene Expression Regulation, Leukemic/drug effects
MH  - HL-60 Cells/drug effects
MH  - Humans
MH  - Ligands
MH  - Macrophage-1 Antigen/biosynthesis/genetics
MH  - Molecular Structure
MH  - Neoplasm Proteins/biosynthesis/*drug effects/genetics
MH  - Neoplastic Stem Cells/*drug effects/pathology
MH  - Protein Multimerization
MH  - Receptors, Retinoic Acid/chemistry/*drug effects
MH  - Retinoic Acid Receptor alpha
MH  - Retinoid X Receptors
MH  - Retinoids/chemical synthesis/*pharmacology
MH  - Signal Transduction/drug effects
MH  - Tetrahydronaphthalenes/chemical synthesis/*pharmacology
MH  - Transcription Factor AP-1/metabolism
MH  - Transcription Factors/chemistry/*drug effects
MH  - Tretinoin/*pharmacology
MH  - Tumor Cells, Cultured/drug effects
EDAT- 1996/03/01 00:00
MHDA- 1996/03/01 00:01
CRDT- 1996/03/01 00:00
PHST- 1996/03/01 00:00 [pubmed]
PHST- 1996/03/01 00:01 [medline]
PHST- 1996/03/01 00:00 [entrez]
AID - S0006-4971(20)65309-5 [pii]
PST - ppublish
SO  - Blood. 1996 Mar 1;87(5):1977-84.