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首页> 外文期刊>Leukemia Research and Treatment >In VitroCharacterization 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
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In VitroCharacterization 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

机译：丙戊酸，ATRA和阿糖胞苷在人类急性髓性白血病中用于疾病稳定化的体外表征：药物对内皮和成骨细胞的抗增殖作用以及血管内皮细胞调节性调节剂的释放

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The combined use of the histone deacetylase inhibitor valproic acid (VPA), the retinoic acid receptor-αagonist all-trans retinoic acid (ATRA), and the deoxyribonucleic acid polymerase-αinhibitor 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-dosein vivotreatment. 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.
机译：现在考虑将组蛋白脱乙酰基酶抑制剂丙戊酸（VPA），视黄酸受体-α激动剂全反式视黄酸（ATRA）和脱氧核糖核酸聚合酶-α抑制剂阿糖胞苷（Ara-C）组合使用来稳定疾病急性髓细胞性白血病（AML）。白血病的发生和白血病细胞的化学抗性似乎受到骨髓中相邻基质细胞的支持，因此我们研究了这些药物对人原代内皮细胞和成骨细胞Cal72细胞系的影响。结果表明，VPA和Ara-C具有抗增殖作用，并且在低浓度（对应于低剂量体内治疗期间发现的血清水平）下观察到Ara-C的抗增殖/细胞毒性作用。此外，在内皮迁移和管形成的功能测定中，VPA引起抗血管生成作用，而ATRA引起促血管生成作用。最后，VPA和ATRA改变了血管生成介质的内皮细胞释放。 ATRA增加CXCL8，PDGF-AA和VEGF-D的水平，而VPA降低VEGF-D和PDGF-AA / BB的水平，两种药物均降低MMP-2的水平。这些介体中的几种可增强AML细胞增殖和/或参与AML诱导的骨髓血管生成，因此对基质细胞的直接药理作用可能会间接促进这种三联药物组合的总体抗白血病活性。

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