Effects of novel retinoic acid compound, 9-cis-retinoic acid, on proliferation, differentiation, and expression of retinoic acid receptor-α and retinoid X receptor-α RNA by HL-60 cells

Masahiro Kizaki, Yasuo Ikeda, Ryuji Tanosaki, Hideaki Nakajima, Minoru Morikawa, Akiko Sakashita, H. Phillip Koeffler

Research output: Contribution to journalArticle

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Abstract

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-α and RXR-α 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 (≧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-α 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-α mRNA accumulation in a dose-dependent manner.

Original languageEnglish
Pages (from-to)3592-3599
Number of pages8
JournalBlood
Volume82
Issue number12
Publication statusPublished - 1993 Dec 15

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Retinoid X Receptors
Retinoic Acid Receptors
HL-60 Cells
Tretinoin
Retinoids
RNA
CD11b Antigens
Cell Differentiation
Cells
Growth
Nitroblue Tetrazolium
Messenger RNA
Stereoisomerism
Acute Promyelocytic Leukemia
Aptitude
alitretinoin
Genes
Ligands
Plasmas
Cell Proliferation

ASJC Scopus subject areas

  • Hematology

Cite this

Effects of novel retinoic acid compound, 9-cis-retinoic acid, on proliferation, differentiation, and expression of retinoic acid receptor-α and retinoid X receptor-α RNA by HL-60 cells. / Kizaki, Masahiro; Ikeda, Yasuo; Tanosaki, Ryuji; Nakajima, Hideaki; Morikawa, Minoru; Sakashita, Akiko; Koeffler, H. Phillip.

In: Blood, Vol. 82, No. 12, 15.12.1993, p. 3592-3599.

Research output: Contribution to journalArticle

Kizaki, Masahiro ; Ikeda, Yasuo ; Tanosaki, Ryuji ; Nakajima, Hideaki ; Morikawa, Minoru ; Sakashita, Akiko ; Koeffler, H. Phillip. / Effects of novel retinoic acid compound, 9-cis-retinoic acid, on proliferation, differentiation, and expression of retinoic acid receptor-α and retinoid X receptor-α RNA by HL-60 cells. In: Blood. 1993 ; Vol. 82, No. 12. pp. 3592-3599.
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abstract = "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-α and RXR-α 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 (≧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-α 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-α mRNA accumulation in a dose-dependent manner.",
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AU - Ikeda, Yasuo

AU - Tanosaki, Ryuji

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AU - Morikawa, Minoru

AU - Sakashita, Akiko

AU - Koeffler, H. Phillip

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N2 - 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-α and RXR-α 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 (≧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-α 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-α mRNA accumulation in a dose-dependent manner.

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