Pharicin B stabilizes retinoic acid receptor-α and presents synergistic differentiation induction with ATRA in myeloid leukemic cells

Blood ◽  
2010 ◽  
Vol 116 (24) ◽  
pp. 5289-5297 ◽  
Author(s):  
Zhi-Min Gu ◽  
Ying-Li Wu ◽  
Mei-Yi Zhou ◽  
Chuan-Xu Liu ◽  
Han-Zhang Xu ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Cell Lines ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
Leukemic Cells ◽  
Natural Ligand ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Induction Of Differentiation ◽  
Retinoic Acid Receptor Α

Abstract All-trans retinoic acid (ATRA), a natural ligand for the retinoic acid receptors (RARs), induces clinical remission in most acute promyelocytic leukemia (APL) patients through the induction of differentiation and/or eradication of leukemia-initiating cells. Here, we identify a novel natural ent-kaurene diterpenoid derived from Isodon pharicus leaves, called pharicin B, that can rapidly stabilize RAR-α protein in various acute myeloid leukemic (AML) cell lines and primary leukemic cells from AML patients, even in the presence of ATRA, which is known to induce the loss of RAR-α protein. Pharicin B also enhances ATRA-dependent the transcriptional activity of RAR-α protein in the promyelocytic leukemia–RARα–positive APL cell line NB4 cells. We also showed that pharicin B presents a synergistic or additive differentiation-enhancing effect when used in combination with ATRA in several AML cell lines and, especially, some primary leukemic cells from APL patients. In addition, pharicin B can overcome retinoid resistance in 2 of 3 NB4-derived ATRA-resistant subclones. These findings provide a good example for chemical biology–based investigations of pathophysiological and therapeutic significances of RAR-α and PML-RAR-α proteins. The effectiveness of the ATRA/pharicin B combination warrants further investigation on their use as a therapeutic strategy for AML patients.

scholarly journals CCAAT/enhancer binding proteins alpha and epsilon cooperate with all-trans retinoic acid in therapy but differ in their antileukemic activities

Blood ◽  
2006 ◽  
Vol 108 (7) ◽  
pp. 2416-2419 ◽  
Author(s):  
Young-Jin Lee ◽  
Letetia C. Jones ◽  
Nikolai A. Timchenko ◽  
Danilo Perrotti ◽  
Daniel G. Tenen ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Binding Proteins ◽  
Retinoic Acid Receptor ◽  
Chromosomal Translocation ◽  
Promyelocytic Leukemia ◽  
Leukemic Cells ◽  
Enhancer Binding Proteins ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Retinoic Acid Receptor Α

Abstract CCAAT/enhancer binding proteins (C/EBPs) play critical roles in myelopoiesis. Dysregulation of these proteins likely contributes to the pathogenesis of myeloid disorders characterized by a block in granulopoiesis. In one such disease, acute promyelocytic leukemia (APL), a promyelocytic leukemia–retinoic acid receptor α (PML-RARα) fusion protein is expressed as a result of a t(15;17) chromosomal translocation. Treatment of PML-RARα leukemic cells with all-trans retinoic acid (ATRA) causes them to differentiate into mature neutrophils, an effect thought to be mediated by C/EBPs. In this study, we assess the potential for cooperativity between increased C/EBP activity and ATRA therapy. We demonstrate that although both C/EBPα and C/EBPϵ can significantly prolong survival in a mouse model of APL, they are not functionally equivalent in this capacity. We also show that forced expression of C/EBPα or C/EBPϵ in combination with ATRA treatment has a synergistic effect on survival of leukemic mice compared with either therapy alone.

Regulation of S100A10 by the PML-RAR-α oncoprotein

Blood ◽  
2011 ◽  
Vol 117 (15) ◽  
pp. 4095-4105 ◽  
Author(s):  
Paul A. O'Connell ◽  
Patricia A. Madureira ◽  
Jason N. Berman ◽  
Robert S. Liwski ◽  
David M. Waisman
Keyword(s):  
Retinoic Acid ◽  
Cell Surface ◽  
Fibrinolytic Activity ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Retinoic Acid Receptor Α ◽  
First Time ◽  
Distinct Subtype

Abstract Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia that results from the expression of the promyelocytic leukemia–retinoic acid receptor α (PML-RAR-α) oncoprotein. It is characterized by severe hemorrhagic complications due in part to excessive fibrinolysis, resulting from the excessive generation of the fibrinolytic enzyme, plasmin, at the cell surface of the PML cells. The treatment of patients with all-trans retinoic acid (ATRA) effectively ameliorates the disease by promoting the destruction of the PML-RAR-α oncoprotein. In the present study we show for the first time that the plasminogen receptor, S100A10, is present on the extracellular surface of APL cells and is rapidly down-regulated in response to all-trans retinoic acid. The loss of S100A10 is concomitant with a loss in fibrinolytic activity. Furthermore, the induced expression of the PML-RAR-α oncoprotein increased the expression of cell surface S100A10 and also caused a dramatic increase in fibrinolytic activity. Depletion of S100A10 by RNA interference effectively blocked the enhanced fibrinolytic activity observed after induction of the PML-RAR-α oncoprotein. These experiments show that S100A10 plays a crucial role in the generation of plasmin leading to fibrinolysis, thus providing a link to the clinical hemorrhagic phenotype of APL.

scholarly journals All-trans retinoic acid upregulates thrombomodulin and downregulates tissue-factor expression in acute promyelocytic leukemia cells: distinct expression of thrombomodulin and tissue factor in human leukemic cells

Blood ◽  
1994 ◽  
Vol 84 (9) ◽  
pp. 3001-3009 ◽  
Author(s):  
T Koyama ◽  
S Hirosawa ◽  
N Kawamata ◽  
S Tohda ◽  
N Aoki
Keyword(s):  
Retinoic Acid ◽  
Tissue Factor ◽  
Acute Promyelocytic Leukemia ◽  
Cell Lines ◽  
Promyelocytic Leukemia ◽  
Leukemic Cells ◽  
Monocytic Leukemia ◽  
Nb4 Cells ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

The expressions of thrombomodulin (TM) and tissue factor (TF) by all- trans retinoic acid (ATRA) were studied in human leukemic cell lines including NB4 (acute promyelocytic leukemia) and U937 (monoblastic leukemia). ATRA remarkably upregulated TM antigen expression in cell lysates as well as TM cofactor activity on the cell surfaces of NB4. The level of TM mRNA in NB4 cells was increased by ATRA. Inherently procoagulant NB4 cells contained markedly higher content of TF, which was efficiently reduced by ATRA. Modest increase of TM and decrease of TF were observed when NB4 cells were treated with dibutyryl cyclic adenosine monophosphate (dbcAMP). On the other hand, both ATRA and dbcAMP showed dramatic increase of TM antigen level and modest decrease of TF antigen in U937 cells. These results suggest that ATRA regulates expressions of TM and TF antigens and activity in NB4 and U937 cell lines, and provide evidence for a potential efficiency of ATRA as a preventive and therapeutic agent for disseminated intravascular coagulation in promyelocytic and monocytic leukemia.

scholarly journals All-trans retinoic acid upregulates thrombomodulin and downregulates tissue-factor expression in acute promyelocytic leukemia cells: distinct expression of thrombomodulin and tissue factor in human leukemic cells

Blood ◽  
1994 ◽  
Vol 84 (9) ◽  
pp. 3001-3009 ◽  
Author(s):  
T Koyama ◽  
S Hirosawa ◽  
N Kawamata ◽  
S Tohda ◽  
N Aoki
Keyword(s):  
Retinoic Acid ◽  
Tissue Factor ◽  
Acute Promyelocytic Leukemia ◽  
Cell Lines ◽  
Promyelocytic Leukemia ◽  
Leukemic Cells ◽  
Monocytic Leukemia ◽  
Nb4 Cells ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Abstract The expressions of thrombomodulin (TM) and tissue factor (TF) by all- trans retinoic acid (ATRA) were studied in human leukemic cell lines including NB4 (acute promyelocytic leukemia) and U937 (monoblastic leukemia). ATRA remarkably upregulated TM antigen expression in cell lysates as well as TM cofactor activity on the cell surfaces of NB4. The level of TM mRNA in NB4 cells was increased by ATRA. Inherently procoagulant NB4 cells contained markedly higher content of TF, which was efficiently reduced by ATRA. Modest increase of TM and decrease of TF were observed when NB4 cells were treated with dibutyryl cyclic adenosine monophosphate (dbcAMP). On the other hand, both ATRA and dbcAMP showed dramatic increase of TM antigen level and modest decrease of TF antigen in U937 cells. These results suggest that ATRA regulates expressions of TM and TF antigens and activity in NB4 and U937 cell lines, and provide evidence for a potential efficiency of ATRA as a preventive and therapeutic agent for disseminated intravascular coagulation in promyelocytic and monocytic leukemia.

Pim2 cooperates with PML-RARα to induce acute myeloid leukemia in a bone marrow transplantation model

Blood ◽  
2010 ◽  
Vol 115 (22) ◽  
pp. 4507-4516 ◽  
Author(s):  
Shuchi Agrawal-Singh ◽  
Steffen Koschmieder ◽  
Sandra Gelsing ◽  
Carol Stocking ◽  
Martin Stehling ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Immature Myeloid Cells ◽  
Retinoic Acid Receptor Α ◽  
Transplantation Model

Abstract Although the potential role of Pim2 as a cooperative oncogene has been well described in lymphoma, its role in leukemia has remained largely unexplored. Here we show that high expression of Pim2 is observed in patients with acute promyelocytic leukemia (APL). To further characterize the cooperative role of Pim2 with promyelocytic leukemia/retinoic acid receptor α (PML/RARα), we used a well-established PML-RARα (PRα) mouse model. Pim2 coexpression in PRα-positive hematopoietic progenitor cells (HPCs) induces leukemia in recipient mice after a short latency. Pim2-PRα cells were able to repopulate mice in serial transplantations and to induce disease in all recipients. Neither Pim2 nor PRα alone was sufficient to induce leukemia upon transplantation in this model. The disease induced by Pim2 overexpression in PRα cells contained a slightly higher fraction of immature myeloid cells, compared with the previously described APL disease induced by PRα. However, it also clearly resembled an APL-like phenotype and showed signs of differentiation upon all-trans retinoic acid (ATRA) treatment in vitro. These results support the hypothesis that Pim2, which is also a known target of Flt3-ITD (another gene that cooperates with PML-RARα), cooperates with PRα to induce APL-like disease.

All-trans-retinoic acid induces CD52 expression in acute promyelocytic leukemia

Blood ◽  
2003 ◽  
Vol 101 (5) ◽  
pp. 1977-1980 ◽  
Author(s):  
Shi-Wu Li ◽  
Dongqi Tang ◽  
Kim P. Ahrens ◽  
Jin-Xiong She ◽  
Raul C. Braylan ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Retinoic Acid Receptor ◽  
Leukemia Cell ◽  
Myeloid Cell ◽  
Promyelocytic Leukemia ◽  
Leukemic Cells ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
High Level

It is well known that all-trans-retinoic acid (ATRA) can induce myeloid cell differentiation in acute promyelocytic leukemia (APL) cells. In this study, we found that ATRA treatment of the APL cell line NB4 induced the expression of CD52, both at transcriptional and translational levels. CD52 is a 21- to 28-kDa nonmodulating cell surface glycosylphosphatidylinositol-linked glycoprotein expressed on lymphocytes and monocytes, but not in human myeloid cells. The ATRA-dependent induction of CD52 expression was not observed in non-promyelocytic leukemia cell lines such as K562, U937, and HL-60, suggesting that induction of CD52 by ATRA may be specific to leukemic cells that express promyelocytic leukemia–retinoic acid receptor α (PML-RARα) or are at the promyelocytic stage of myeloid development. Antibodies against CD52 are used therapeutically against lymphocytes in certain leukemias and in patients undergoing transplantation. An ATRA-induced high level of CD52 expression might potentially serve as a novel therapeutic target in treatment of APL.

scholarly journals Enhanced Antiproliferative Effect of Combined Treatment with Calcitriol and All-Trans Retinoic Acid in Relation to Vitamin D Receptor and Retinoic Acid Receptor α Expression in Osteosarcoma Cell Lines

2020 ◽  
Vol 21 (18) ◽  
pp. 6591
Author(s):  
Silvia Paukovcekova ◽  
Dalibor Valik ◽  
Jaroslav Sterba ◽  
Renata Veselska
Keyword(s):  
Retinoic Acid ◽  
Cell Lines ◽  
Retinoic Acid Receptor ◽  
Combined Treatment ◽  
Osteosarcoma Cell ◽  
Osteosarcoma Cells ◽  
Human Osteosarcoma ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Retinoic Acid Receptor Α

The main objective of this study was to analyze changes in the antiproliferative effect of vitamin D3, in the form of calcitriol and calcidiol, via its combined application with all-trans retinoic acid (ATRA) in osteosarcoma cell lines. The response to treatment with calcitriol and calcidiol alone was specific for each cell line. Nevertheless, we observed an enhanced effect of combined treatment with ATRA and calcitriol in the majority of the cell lines. Although the levels of respective nuclear receptors did not correlate with the sensitivity of cells to these drugs, vitamin D receptor (VDR) upregulation induced by ATRA was found in cell lines that were the most sensitive to the combined treatment. In addition, all these cell lines showed high endogenous levels of retinoic acid receptor α (RARα). Our study confirmed that the combination of calcitriol and ATRA can achieve enhanced antiproliferative effects in human osteosarcoma cell lines in vitro. Moreover, we provide the first evidence that ATRA is able to upregulate VDR expression in human osteosarcoma cells. According to our results, the endogenous levels of RARα and VDR could be used as a predictor of possible synergy between ATRA and calcitriol in osteosarcoma cells.

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