Table of Contents
Leukemia Research and Treatment
Volume 2014 (2014), Article ID 143479, 12 pages
Research Article

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

1Department of Clinical Science, Hematology Section, University of Bergen, 5021 Bergen, Norway
2Department of Molecular Biosciences, University of Oslo, 0316 Oslo, Norway
3Department of Biomedicine, University of Bergen, Norway
4Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway

Received 28 July 2013; Accepted 28 October 2013; Published 8 January 2014

Academic Editor: Judith E. Karp

Copyright © 2014 Hilde Kvestad et al. 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.


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.