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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
M Kizaki, Y Ikeda, R Tanosaki, H Nakajima, M Morikawa, A Sakashita and HP Koeffler
Division of Hematology, Keio University School of Medicine, Tokyo, Japan.
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.
Volume 82,
Issue 12,
pp. 3592-3599,
12/15/1993
Copyright © 1993 by The American Society of Hematology
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