Anticoagulant effects of synthetic retinoids

Takatoshi Koyama, Misako Shibakura

Research output: Contribution to journalArticle

Abstract

We have recently found that retinoic acids (RAs) evoke anticoagulant effect by upregulating thrombomodulin (TM) and downregulating tissue factor (TF) expression in acute promyelocytic leukemia (APL) and monoblastic leukemia cells. Two classes of nuclear RA receptors, termed retinoic acid receptors (RARs) and retinoid X receptors, have been identified. Each receptor class consists of three subtypes. We have used several synthetic retinoids to find which receptor subtypes are involved in the regulation of TM and TF expression in APL cells NB4, monoblastic leukemia cells U937 and human umbilical vein endothelial cells (HUVECs). Am80, which does not have a binding affinity to RARγ, Ch55, which does not bind to cytoplasmic retinoic acid binding protein (CRABP), and a specific RARα agonist Ro40-6055, have shown to upregulate TM and downregulate TF in NB4 and U937 cells similar to all-trans RA (ATRA). A specific RARα antagonist Ro41-5253 efficiently suppressed the upregulation of TM by ATRA and Am80 in NB4 cells, U937 cells and HUVECs. In contrast, only when both RARα and RARβ antagonists were preincubated, downregulation of TF by the retinoids was suppressed in NB4 cells. These results indicate the mechanically distinct transactivation and transrepression functions of RARs, the major role of RARα in TM upregulation by retinoids in leukemic cells and HUVECs and the cooperative role of RARα and RARβ in TF downregulation by retinoids. This implies that synthetic retinoids will provide a very useful means to control distinct targets, TM and TF genes, at the level of transcription. Synthetic retinoids may develop as new type of antithrombotic agents which may change the character of cells as well as act as malignant cell differentiation inducers.

Original languageEnglish
Pages (from-to)71-80
Number of pages10
JournalLeukemia and Lymphoma
Volume31
Issue number1-2
Publication statusPublished - 1998
Externally publishedYes

Fingerprint

Retinoic Acid Receptors
Retinoids
Anticoagulants
Thrombomodulin
Thromboplastin
U937 Cells
Human Umbilical Vein Endothelial Cells
Down-Regulation
Acute Promyelocytic Leukemia
Up-Regulation
Tretinoin
Leukemia
Retinoid X Receptors
Fibrinolytic Agents
Transcriptional Activation
Cell Differentiation

Keywords

  • Retinoic acid receptor (RAR)
  • Synthetic retinoids
  • Thrombomodulin (TM)
  • Tissue factor (TF)

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Anticoagulant effects of synthetic retinoids. / Koyama, Takatoshi; Shibakura, Misako.

In: Leukemia and Lymphoma, Vol. 31, No. 1-2, 1998, p. 71-80.

Research output: Contribution to journalArticle

Koyama, Takatoshi ; Shibakura, Misako. / Anticoagulant effects of synthetic retinoids. In: Leukemia and Lymphoma. 1998 ; Vol. 31, No. 1-2. pp. 71-80.
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