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Myeloid differentiation mediated through retinoic acid receptor/retinoic X
receptor (RXR) not RXR/RXR pathway
MI Dawson, E Elstner, M Kizaki, DL Chen, S Pakkala, B Kerner and HP Koeffler
Bio-Organic Chemistry Laboratory, SRI International, Menlo Park, CA.
Retinoids, such as all-trans-retinoic acid and 9-cis-retinoic acid, are
naturally occurring ligands of the nuclear retinoic acid receptors (RARs).
In concert with binding of ligand, these receptors from heterodimers with
the retinoic X receptor (RXR) and transactivate RAR/RXR-responsive genes.
Retinoids can differentiate leukemic cell lines in vitro and induce
clinically complete remissions in patients with acute promyelocytic
leukemia. Synthetic ligands to the RAR and RXR receptors have been
developed that selectively bind and activate RAR/RXR (TTAB) and RXR/RXR
dimers (SR11217). We investigated the affect of these ligands, either alone
or in combination, on in vitro growth and differentiation of cells from the
HL-60, KG-1, THP-1, and WEHI-3 myeloid cell lines as well as on clonal
growth of fresh myeloid leukemic blasts from patients. Clonal inhibition of
proliferation of these cells was studied in soft agar cultures. Cells were
plated in the presence of either one or a combination of retinoids at
concentrations of 10(-5) to 10(-10) mol/L. TTAB inhibited 50% clonal growth
at an effective dose (ED50) that was about 1,000-fold lower than the
concentration of SR11217 required to achieve an ED50 for the same leukemic
cells. Combination of both ligands at a variety of concentrations showed no
synergistic effects. Superoxide production (nitroblue tetrazolium
reduction) and CD11b expression as parameters of differentiation of HL-60
cells were also examined. Results paralleled those of clonal growth, with
SR11217 being markedly less potent than TTAB. These results show that the
ligand selective for RXR-homodimers has little effect on either inducing
differentiation or inhibiting clonal growth of leukemic cells. The
differentiating and antiproliferative effects of retinoids are mainly
induced through RAR/RXR heterodimers, and development of therapeutic
analogs should focus on this category of retinoids.
Volume 84,
Issue 2,
pp. 446-452,
07/15/1994
Copyright © 1994 by The American Society of Hematology
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