Novel retinoic acid, 9-cis retinoic acid, in combination with all-trans retinoic acid is an effective inducer of differentiation of retinoic acid-resistant HL-60 cells

Masahiro Kizaki, Hideaki Nakajima, Shigehisa Mori, Tsuneaki Koike, Minoru Morikawa, Masatsugu Ohta, Masaki Saito, H. Phillip Koeffler, Yasuo Ikeda

Research output: Contribution to journalArticle

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Abstract

Recent studies have shown that a high proportion of patients with acute promyelocytic leukemia (APL) achieve complete remission after treatment with all-trans retinoic acid (RA). Nevertheless, despite an initial good response, most patients that received continuous treatment with alltrans RA relapse and develop RA-resistant disease. The 9-cis RA is a high-affinity ligand for retinoid X receptors (RXRs) and also binds efficiently to retinoic acid receptors (RARs); all-trans RA is a ligand for RARs. Both alone are able to induce differentiation of wild-type HL-60 cells. We found that neither all-trans RA nor 9-cis RA (<2 × 10-6 mol/L) induced differentiation of RA-resistant HL-60 cells into either mature granulocytes or monocytes. However, morphologic differentiation of the RA-resistant HL-60 cells was induced by 10-6 mol/L all-trans RA combined with various concentrations (10-12 to 10-6 mol/L) of 9-cis RA. Electron microscopic examination also confirmed that the combination of both retinoids induced RA-resistant HL-60 cells to differentiate to mature granulocytes. Functional analysis of differentiation (NBT reduction activity) confirmed the necessity of both analogs to induce differentiation. Also, expression of myeloid-specific differentiation antigens (CD11b and CD14) as well as migration inhibitory factor-related protein (MRP)-8/14 mRNAs were upregulated only in the presence of both retinoids in a dose-dependent manner. In these conditions 3H-thymidine incorporation was inhibited and numbers of viable cells were decreased, suggesting that all-trans RA with 9-cis RA may inhibit cell growth and induce differentiation of RA-resistant HL-60 cells into mature granulocytes. These studies suggest that 9-cis RA in combination with all-trans RA is an effective inducer of RA-resistant HL-60 cells and may have implications for both the biology of retinoids and clinical treatment of RA-resistant acute myelogenous leukemia, including APL patients.

Original languageEnglish
Pages (from-to)3289-3297
Number of pages9
JournalBlood
Volume83
Issue number11
Publication statusPublished - 1994 Jun 1
Externally publishedYes

Fingerprint

HL-60 Cells
Tretinoin
Acids
Retinoids
Granulocytes
Acute Promyelocytic Leukemia
Retinoic Acid Receptors
alitretinoin
Calgranulin B
Calgranulin A
Differentiation (calculus)
Ligands
Retinoid X Receptors
Functional analysis
Differentiation Antigens
Cell growth
Acute Myeloid Leukemia
Thymidine
Monocytes
Microscopic examination

ASJC Scopus subject areas

  • Hematology

Cite this

Kizaki, M., Nakajima, H., Mori, S., Koike, T., Morikawa, M., Ohta, M., ... Ikeda, Y. (1994). Novel retinoic acid, 9-cis retinoic acid, in combination with all-trans retinoic acid is an effective inducer of differentiation of retinoic acid-resistant HL-60 cells. Blood, 83(11), 3289-3297.

Novel retinoic acid, 9-cis retinoic acid, in combination with all-trans retinoic acid is an effective inducer of differentiation of retinoic acid-resistant HL-60 cells. / Kizaki, Masahiro; Nakajima, Hideaki; Mori, Shigehisa; Koike, Tsuneaki; Morikawa, Minoru; Ohta, Masatsugu; Saito, Masaki; Koeffler, H. Phillip; Ikeda, Yasuo.

In: Blood, Vol. 83, No. 11, 01.06.1994, p. 3289-3297.

Research output: Contribution to journalArticle

Kizaki, M, Nakajima, H, Mori, S, Koike, T, Morikawa, M, Ohta, M, Saito, M, Koeffler, HP & Ikeda, Y 1994, 'Novel retinoic acid, 9-cis retinoic acid, in combination with all-trans retinoic acid is an effective inducer of differentiation of retinoic acid-resistant HL-60 cells', Blood, vol. 83, no. 11, pp. 3289-3297.
Kizaki, Masahiro ; Nakajima, Hideaki ; Mori, Shigehisa ; Koike, Tsuneaki ; Morikawa, Minoru ; Ohta, Masatsugu ; Saito, Masaki ; Koeffler, H. Phillip ; Ikeda, Yasuo. / Novel retinoic acid, 9-cis retinoic acid, in combination with all-trans retinoic acid is an effective inducer of differentiation of retinoic acid-resistant HL-60 cells. In: Blood. 1994 ; Vol. 83, No. 11. pp. 3289-3297.
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abstract = "Recent studies have shown that a high proportion of patients with acute promyelocytic leukemia (APL) achieve complete remission after treatment with all-trans retinoic acid (RA). Nevertheless, despite an initial good response, most patients that received continuous treatment with alltrans RA relapse and develop RA-resistant disease. The 9-cis RA is a high-affinity ligand for retinoid X receptors (RXRs) and also binds efficiently to retinoic acid receptors (RARs); all-trans RA is a ligand for RARs. Both alone are able to induce differentiation of wild-type HL-60 cells. We found that neither all-trans RA nor 9-cis RA (<2 × 10-6 mol/L) induced differentiation of RA-resistant HL-60 cells into either mature granulocytes or monocytes. However, morphologic differentiation of the RA-resistant HL-60 cells was induced by 10-6 mol/L all-trans RA combined with various concentrations (10-12 to 10-6 mol/L) of 9-cis RA. Electron microscopic examination also confirmed that the combination of both retinoids induced RA-resistant HL-60 cells to differentiate to mature granulocytes. Functional analysis of differentiation (NBT reduction activity) confirmed the necessity of both analogs to induce differentiation. Also, expression of myeloid-specific differentiation antigens (CD11b and CD14) as well as migration inhibitory factor-related protein (MRP)-8/14 mRNAs were upregulated only in the presence of both retinoids in a dose-dependent manner. In these conditions 3H-thymidine incorporation was inhibited and numbers of viable cells were decreased, suggesting that all-trans RA with 9-cis RA may inhibit cell growth and induce differentiation of RA-resistant HL-60 cells into mature granulocytes. These studies suggest that 9-cis RA in combination with all-trans RA is an effective inducer of RA-resistant HL-60 cells and may have implications for both the biology of retinoids and clinical treatment of RA-resistant acute myelogenous leukemia, including APL patients.",
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