Anticoagulant effects of retinoic acids on leukemia cells

Saitô, Takako; Koyama, Takatoshi; Nagata, Kaoru; Kamiyama, Ryuichi; Hirosawa, Shinsaku

doi:10.1182/blood.v87.2.657.bloodjournal872657

Cited by 48 publications

(24 citation statements)

References 17 publications

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“…Derivates of retinoic acid have been shown earlier to have anticoagulant effects on monocytic cells (24,25). It has been reported, that ATRA up-regulates thrombomodulin and down-regulates T F expression in primary leukaemic cells (26), and in the established leukaemic cell lines of the monocytic lineage (25). Treatment of acute promyelocytic leukaemia cells with ATRA has been known to counteract the disease-associated coagulopathy and is widely used for treatment of patients (27).…”

Section: Discussionmentioning

confidence: 99%

Induction of differentiation in U‐937 and NB4 cells is associated with inhibition of tissue factor production

Tenno

Öberg

Nilsson

et al. 1999

European J of Haematology

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Tissue factor (TF) production is under strict control in mature monocytic cells. However, constitutive expression of TF can be found in myelomonocytic cells and in haematopoietic cells arrested at an early stage of differentiation. In this paper we show that TF expression is down‐regulated during the monocyte/granulocyte differentiation process, using the human monoblastic U‐937 and the acute promyelocytic leukaemia NB4 cell lines as models. Expression of TF mRNA, protein and procoagulant activity (PCA) was constitutively high in untreated cells. Exposure of U‐937 cells to 1 α,25‐dihydroxycholecalciferol (VitD3) and all‐trans retinoic acid (ATRA) resulted in down‐regulation of TF expression and PCA. In NB4 cells induction by ATRA, but not VitD3, resulted in the down‐regulation of TF expression and PCA. Consistent with this, induction of terminal differentiation, as confirmed by the expression of differentiation associated antigens and cell cycle arrest, was inversely correlated to TF expression in U‐937 and NB4 cells. Moreover, terminally differentiated U‐937 cells retained the capacity to respond to inflammatory mediators, i.e. lipopolysaccharide and interferon‐γ, by a rapid increase in TF expression. In conclusion, we show that not only ATRA but also VitD3 is a potent suppressor of monocytic TF expression and thus might have potential clinical use for the treatment of coagulopathies.

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Section: Discussionmentioning

confidence: 99%

Induction of differentiation in U‐937 and NB4 cells is associated with inhibition of tissue factor production

Tenno

Öberg

Nilsson

et al. 1999

European J of Haematology

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“…18 ATRA is an effective downregulator for monocyte TF 19 and for TF and cancer procoagulant in APL cells. 8,9,20 Clinical application of retinoids is expected to be useful as a new strategy of antithrombotic therapy which changes the procoagulant character of cells including malignant cells, diseased endothelial cells, 7 and mono cytes by regulating TM and TF expression at the level of transcription. Aging is a very crucial problem in a mod ern world.…”

Section: Discussionmentioning

confidence: 99%

“…Anticoagulant effects of ATRA (i.e., upregu lation of TM expression and downregulation of TF ex pression) were observed not only in established cell lines of specific subtypes (M3 and M5) but also in freshly iso lated cells of other types of AML in addition to M3 and M5 subtypes. 9 The biological effects of ATRA are mediated by its binding to the retinoic acid receptors (RARs). A stereoisomer of RA, 9-cis RA, has been found to be a high-affinity ligand for RARs and retinoid X receptors (RXRs).…”

Section: Effects Of Atra and Its Isomers On Tm And Tf Expression In Amentioning

confidence: 99%

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Anticoagulant Effects of Synthetic Retinoids and Activated Vitamin D₃

Koyama¹,

Hirosawa²

1998

Semin Thromb Hemost

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We have recently found that retinoic acids (RAs) evoke an anticoagulant effect by upregulating thrombomodulin (TM) and downregulating expression of tissue factor (TF) 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 already 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 RARgamma; Ch55, which does not bind to cytoplasmic retinoic acid-binding protein (CRABP); and a specific RARalpha agonist, Ro40-6055, have been shown to upregulate TM and downregulate TF in NB4 and U937 cells similar to all-trans RA (ATRA). A specific RARalpha 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 RARalpha and RARbeta antagonists were preincubated, downregulation of TF by the retinoids was suppressed in NB4 cells. Furthermore, 1,25(OH)2D3 has been shown to have anticoagulant effects on several monocytic leukemia cells and monocytes similar to RAs. These results indicate the mechanically distinct transactivation and transrepression functions of RARs, the major role of RARalpha in TM upregulation by retinoids in leukemic cells and HUVECs, and the cooperative role of RARalpha and RARbeta in TF downregulation by retinoids. It is also implied that synthetic retinoids and vitamin D derivatives will provide very useful means to control distinct targets--TM and TF genes--at the level of transcription. Synthetic retinoids and vitamin D derivatives may develop as new types of antithrombotic and antiatherosclerotic agents which change the character of cells as well as malignant cell differentiation inducers.

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“…Our group and another have characterized several functional elements in the 5 H -¯anking sequences which are essential for transcriptional regulation (Tazawa et al, 1993;Yu et al, 1992). We also have found a region which displays silencer activity and an element which is responsive to cyclic AMP (Tazawa et al, 1994 leukaemia treated with all-trans retinoic acids may be important for the remarkable improvement of associated disseminated intravascular coagulation (Koyama et al, 1994;Saito et al, 1996;Shibakura et al, 1997).…”

mentioning

confidence: 87%

Thrombomodulin with the Asp468Tyr mutation is expressed on the cell surface with normal cofactor activity for protein C activation

Nakazawa¹,

Koyama²,

Saitô³

et al. 1999

Br J Haematol

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Summary. Thrombomodulin (TM) is an endothelial cell glycoprotein that acts as an anticoagulant. Mutation in the TM gene is a potential risk factor for thrombosis. The ®rst TM mutation identi®ed was a heterozygous substitution of T for G at nucleotide position 1456, which predicted Asp468 with Tyr in a Ser/Thr-rich domain. To evaluate the reported TM gene mutation as a possible cause of thrombosis, we transiently tranfected a vector for TM gene carrying the mutation to mammalian COS7 cells.TM antigen levels in lysates of cells transfected with variant TM were comparable to those in preparations of normal TM. The TM cofactor activity for protein C (PC) activation on the variant TM-expressing cells was similar to that of the control. The Michaelis constant K m and V max. of variant TM for PC activation were shown to be similar compared to those of normal TM. The af®nity of each TM for thrombin in PC activation was also similar. We obtained several stable cell lines expressing normal and variant TM. Lysate of the cell lines with normal and variant TM genes had a similar expression level of TM antigen. Pulse-chase analysis showed that normal and variant TM were glycosylated and resistant to endoglycosidase H, indicating that the variant TM was expressed on the cell surface in a mature form.Variant TM protein is apparently expressed on the cell surface with normal cofactor activity for PC activation. It is unlikely that the TM variant directly causes thrombosis by mechanism of reduced expression or impaired cofactor activity for PC activation, which comprises a major anticoagulant activity of TM.

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Anticoagulant effects of retinoic acids on leukemia cells

Cited by 48 publications

References 17 publications

Induction of differentiation in U‐937 and NB4 cells is associated with inhibition of tissue factor production

Induction of differentiation in U‐937 and NB4 cells is associated with inhibition of tissue factor production

Anticoagulant Effects of Synthetic Retinoids and Activated Vitamin D₃

Thrombomodulin with the Asp468Tyr mutation is expressed on the cell surface with normal cofactor activity for protein C activation

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Anticoagulant effects of retinoic acids on leukemia cells

Cited by 48 publications

References 17 publications

Induction of differentiation in U‐937 and NB4 cells is associated with inhibition of tissue factor production

Induction of differentiation in U‐937 and NB4 cells is associated with inhibition of tissue factor production

Anticoagulant Effects of Synthetic Retinoids and Activated Vitamin D3

Thrombomodulin with the Asp468Tyr mutation is expressed on the cell surface with normal cofactor activity for protein C activation

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Anticoagulant Effects of Synthetic Retinoids and Activated Vitamin D₃