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Blood, Vol. 93 No. 6 (March 15), 1999:
pp. 2057-2066
Effects of Novel RAR- and RXR-Selective Retinoids on Myeloid Leukemic
Proliferation and Differentiation In Vitro
Masaaki Shiohara,
Marcia I. Dawson,
Peter D. Hobbs,
Nobukuni Sawai,
Tsukasa Higuchi,
Kenichi Koike,
Atsushi Komiyama, and
H. Phillip Koeffler
From the Department of Pediatrics, Shinshu University School of
Medicine, Matsumoto Japan; Retinoid Program, SRI International, Menlo
Park, CA; the Division of Hematology/Oncology, Cedars-Sinai Medical
Center, University of California at Los Angeles School of Medicine, Los
Angeles, CA.
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  ,  , and  , 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 RAR and ,
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/EBP 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.
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