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.
abstract: 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.
authors: Department of Clinical Science, Hematology Section, University of Bergen, 5021 Bergen, Norway.
authors: Hilde
authors: 0000-0003-3707-1788
authors: H
authors: Kvestad
authors: Department of Molecular Biosciences, University of Oslo, 0316 Oslo, Norway ; Department of Biomedicine, University of Bergen, Norway.
authors: Lasse
authors: 0000-0002-0725-7242
authors: L
authors: Evensen
authors: Department of Biomedicine, University of Bergen, Norway.
authors: James B
authors: JB
authors: Lorens
authors: Department of Clinical Science, Hematology Section, University of Bergen, 5021 Bergen, Norway ; Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway.
authors: Oystein
authors: O
authors: Bruserud
authors: Department of Clinical Science, Hematology Section, University of Bergen, 5021 Bergen, Norway ; Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway.
authors: Kimberley J
authors: KJ
authors: Hatfield