Antimyeloma effects of resveratrol through inhibition of angiogenesis.
Antimyeloma effects of resveratrol through inhibition of angiogenesis.
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DOI：
10.1097/00029330-200710010-00006
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发表时间：
2007-10
影响因子：
6.1
通讯作者：
Yu Hu;Chunyan Sun;Jing Huang;L. Hong;Lu Zhang;Zhang‐bo Chu
中科院分区：
文献类型：
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作者：
Yu Hu;Chunyan Sun;Jing Huang;L. Hong;Lu Zhang;Zhang‐bo Chu
背景技术在多发性骨髓瘤（MM）中，骨髓血管生成与肿瘤进展平行并与疾病活动相关。最近的研究证明白藜芦醇在体外和体内具有抗血管生成活性。在本研究中，我们研究了白藜芦醇对骨髓瘤细胞依赖性血管生成的影响以及白藜芦醇对RPMI 8226细胞的一些重要血管生成因子的影响。方法将RPMI 8226细胞与人脐静脉内皮细胞（HUVEC）共培养，评价骨髓瘤细胞对血管生成的影响。用不同浓度的白藜芦醇（6.25-50.00μmol/L）处理RPMI 8226细胞不同时间（12-72小时）。采用逆转录聚合酶链反应（RT-PCR）检测血管内皮生长因子（VEGF）、碱性成纤维细胞生长因子（bFGF）、金属蛋白酶（MMP）-2和MMP-9 mRNA。使用明胶酶谱分析 MMP-2 和 MMP-9 活性。通过酶联免疫吸附测定（ELISA）对培养基中细胞分泌的 VEGF 和 bFGF 蛋白进行定量。结果与RPMI 8226细胞共培养后，HUVECs的细胞增殖、迁移和分化显着增加。白藜芦醇以剂量依赖性方式抑制与骨髓瘤细胞共培养的 HUVEC 的增殖、迁移和管形成。用白藜芦醇处理 RPMI 8226 细胞会导致 MMP-2 和 MMP-9 活性降低。白藜芦醇以剂量和时间依赖性方式抑制 VEGF 和 bFGF 蛋白表达。此外，用不同浓度的白藜芦醇处理的细胞中 VEGF、bFGF、MMP-2 和 MMP-9 mRNA 水平降低，证实了其在基因表达水平上的抗血管生成作用。结论白藜芦醇通过调节VEGF、bFGF、MMP-2和MMP-9的表达和分泌来抑制多发性骨髓瘤血管生成。白藜芦醇可能是治疗多发性骨髓瘤的潜在候选者。
BACKGROUND In multiple myeloma (MM), bone marrow angiogenesis parallels tumour progression and correlates with disease activity. Recent studies have proved resveratrol possesses antiangiogenic activity in vitro and in vivo. In this study, we examined the effects of resveratrol on myeloma cell dependent angiogenesis and the effects of resveratrol on some important angiogenic factors of RPMI 8226 cells. METHODS RPMI 8226 cells were cocultured with human umbilical vein endothelial cells (HUVECs) to evaluate the effects of myeloma cells on angiogenesis. The RPMI 8226 cells were treated with various concentrations of resveratrol (6.25 - 50.00 micromol/L) for different times (12 - 72 hours). Reverse transcriptase polymerase chain reaction (RT-PCR) was used to assay vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), metalloproteinases (MMP)-2 and MMP-9 mRNA. Gelatin zymography was used to analyze MMP-2 and MMP-9 activity. VEGF and bFGF proteins secreted by the cells in the medium were quantified by enzyme linked immunosorbent assay (ELISA). RESULTS Cell proliferation, migration and differentiation of HUVECs markedly increased by coculture with RPMI 8226 cells. Resveratrol inhibited proliferation, migration and tube formation of HUVECs cocultured with myeloma cells in a dose dependent manner. Treatment of RPMI 8226 cells with resveratrol caused a decrease in MMP-2 and MMP-9 activity. Resveratrol inhibited VEGF and bFGF protein expression in a dose and time dependent manner. Furthermore, decreased levels of VEGF, bFGF, MMP-2 and MMP-9 mRNA from cells treated with various concentrations of resveratrol confirmed its antiangiogenic action at the level of gene expression. CONCLUSIONS Resveratrol inhibits multiple myeloma angiogenesis by regulating expression and secretion of VEGF, bFGF, MMP-2 and MMP-9. Resveratrol may be a potential candidate for the treatment of multiple myeloma.