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In Vitro Characterization of Valproic Acid, ATRA, and Cytarabine Used for Disease-Stabilization in Human Acute Myeloid Leukemia: Antiproliferative Effects of Drugs on Endothelial and Osteoblastic Cells and Altered Release of Angioregulatory Mediators by Endothelial Cells

The combined use of the histone deacetylase inhibitor valproic acid (VPA), the retinoic acid receptor-α agonist all-trans retinoic acid (ATRA), and the deoxyribonucleic acid polymerase-α inhibitor cytarabine (Ara-C) is now considered for disease-stabilizing treatment of acute myeloid leukemia (AML)....

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Autores principales: Kvestad, Hilde, Evensen, Lasse, Lorens, James B., Bruserud, Øystein, Hatfield, Kimberley J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi Publishing Corporation 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3910457/
https://www.ncbi.nlm.nih.gov/pubmed/24527217
http://dx.doi.org/10.1155/2014/143479
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author Kvestad, Hilde
Evensen, Lasse
Lorens, James B.
Bruserud, Øystein
Hatfield, Kimberley J.
author_facet Kvestad, Hilde
Evensen, Lasse
Lorens, James B.
Bruserud, Øystein
Hatfield, Kimberley J.
author_sort Kvestad, Hilde
collection PubMed
description The combined use of the histone deacetylase inhibitor valproic acid (VPA), the retinoic acid receptor-α agonist all-trans retinoic acid (ATRA), and the deoxyribonucleic acid polymerase-α inhibitor cytarabine (Ara-C) is now considered for disease-stabilizing treatment of acute myeloid leukemia (AML). Leukemogenesis and leukemia cell chemoresistance seem to be supported by neighbouring stromal cells in the bone marrow, and we have therefore investigated the effects of these drugs on primary human endothelial cells and the osteoblastic Cal72 cell line. The results show that VPA and Ara-C have antiproliferative effects, and the antiproliferative/cytotoxic effect of Ara-C was seen at low concentrations corresponding to serum levels found during low-dose in vivo treatment. Furthermore, in functional assays of endothelial migration and tube formation VPA elicited an antiangiogenic effect, whereas ATRA elicited a proangiogenic effect. Finally, VPA and ATRA altered the endothelial cell release of angiogenic mediators; ATRA increased levels of CXCL8, PDGF-AA, and VEGF-D, while VPA decreased VEGF-D and PDGF-AA/BB levels and both drugs reduced MMP-2 levels. Several of these mediators can enhance AML cell proliferation and/or are involved in AML-induced bone marrow angiogenesis, and direct pharmacological effects on stromal cells may thus indirectly contribute to the overall antileukemic activity of this triple drug combination.
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spelling pubmed-39104572014-02-13 In Vitro Characterization of Valproic Acid, ATRA, and Cytarabine Used for Disease-Stabilization in Human Acute Myeloid Leukemia: Antiproliferative Effects of Drugs on Endothelial and Osteoblastic Cells and Altered Release of Angioregulatory Mediators by Endothelial Cells Kvestad, Hilde Evensen, Lasse Lorens, James B. Bruserud, Øystein Hatfield, Kimberley J. Leuk Res Treatment Research Article The combined use of the histone deacetylase inhibitor valproic acid (VPA), the retinoic acid receptor-α agonist all-trans retinoic acid (ATRA), and the deoxyribonucleic acid polymerase-α inhibitor cytarabine (Ara-C) is now considered for disease-stabilizing treatment of acute myeloid leukemia (AML). Leukemogenesis and leukemia cell chemoresistance seem to be supported by neighbouring stromal cells in the bone marrow, and we have therefore investigated the effects of these drugs on primary human endothelial cells and the osteoblastic Cal72 cell line. The results show that VPA and Ara-C have antiproliferative effects, and the antiproliferative/cytotoxic effect of Ara-C was seen at low concentrations corresponding to serum levels found during low-dose in vivo treatment. Furthermore, in functional assays of endothelial migration and tube formation VPA elicited an antiangiogenic effect, whereas ATRA elicited a proangiogenic effect. Finally, VPA and ATRA altered the endothelial cell release of angiogenic mediators; ATRA increased levels of CXCL8, PDGF-AA, and VEGF-D, while VPA decreased VEGF-D and PDGF-AA/BB levels and both drugs reduced MMP-2 levels. Several of these mediators can enhance AML cell proliferation and/or are involved in AML-induced bone marrow angiogenesis, and direct pharmacological effects on stromal cells may thus indirectly contribute to the overall antileukemic activity of this triple drug combination. Hindawi Publishing Corporation 2014 2014-01-08 /pmc/articles/PMC3910457/ /pubmed/24527217 http://dx.doi.org/10.1155/2014/143479 Text en Copyright © 2014 Hilde Kvestad et al. https://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Kvestad, Hilde
Evensen, Lasse
Lorens, James B.
Bruserud, Øystein
Hatfield, Kimberley J.
In Vitro Characterization of Valproic Acid, ATRA, and Cytarabine Used for Disease-Stabilization in Human Acute Myeloid Leukemia: Antiproliferative Effects of Drugs on Endothelial and Osteoblastic Cells and Altered Release of Angioregulatory Mediators by Endothelial Cells
title In Vitro Characterization of Valproic Acid, ATRA, and Cytarabine Used for Disease-Stabilization in Human Acute Myeloid Leukemia: Antiproliferative Effects of Drugs on Endothelial and Osteoblastic Cells and Altered Release of Angioregulatory Mediators by Endothelial Cells
title_full In Vitro Characterization of Valproic Acid, ATRA, and Cytarabine Used for Disease-Stabilization in Human Acute Myeloid Leukemia: Antiproliferative Effects of Drugs on Endothelial and Osteoblastic Cells and Altered Release of Angioregulatory Mediators by Endothelial Cells
title_fullStr In Vitro Characterization of Valproic Acid, ATRA, and Cytarabine Used for Disease-Stabilization in Human Acute Myeloid Leukemia: Antiproliferative Effects of Drugs on Endothelial and Osteoblastic Cells and Altered Release of Angioregulatory Mediators by Endothelial Cells
title_full_unstemmed In Vitro Characterization of Valproic Acid, ATRA, and Cytarabine Used for Disease-Stabilization in Human Acute Myeloid Leukemia: Antiproliferative Effects of Drugs on Endothelial and Osteoblastic Cells and Altered Release of Angioregulatory Mediators by Endothelial Cells
title_short In Vitro Characterization of Valproic Acid, ATRA, and Cytarabine Used for Disease-Stabilization in Human Acute Myeloid Leukemia: Antiproliferative Effects of Drugs on Endothelial and Osteoblastic Cells and Altered Release of Angioregulatory Mediators by Endothelial Cells
title_sort in vitro characterization of valproic acid, atra, and cytarabine used for disease-stabilization in human acute myeloid leukemia: antiproliferative effects of drugs on endothelial and osteoblastic cells and altered release of angioregulatory mediators by endothelial cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3910457/
https://www.ncbi.nlm.nih.gov/pubmed/24527217
http://dx.doi.org/10.1155/2014/143479
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