Department of Hematology, The 2nd Hospital of Hebei Medical University, 215, Heping Xi Road, Shijiazhuang 050000, People's Republic of China.
Int J Hematol. 2010 Nov;92(4):587-97. doi: 10.1007/s12185-010-0697-3. Epub 2010 Oct 14.
Multiple myeloma (MM) remains an incurable plasma cell disorder to date; therefore, new biologically target-based therapies are in urgent demand. Our previous studies showed that the antimalarial artesunate (ART) possessed anti-myeloma effect by inhibiting proliferation and inducing apoptosis of myeloma cells. The present study evaluated the effect of ART on human myeloma cell-induced angiogenesis and elucidated its mechanism. The human umbilical vein endothelial cells (HUVECs) migration test, aortic sprouting in fibrin gel in vitro and chicken chorioallantoic membrane (CAM) neovascularization in vivo model were used to examine the effect of ART on angiogenesis induced by human myeloma cells. The results showed that ART could inhibit HUVECs migration, even at a lower concentration (3 μmol/l, P < 0.01, compared with the result of control group), and suppress efficiently the angiogenic ability of myeloma RPMI8226 cells in a dose-dependent pattern (3-12 μmol/l, P < 0.05). The levels of VEGF and Ang-1 in the conditioned medium (CM) were quantified by enzyme-linked immunosorbent assay (ELISA). The results confirmed that 3 μmol/l ART could significantly decrease VEGF and Ang-1 secretion by RPMI8226 cells (P < 0.05), which correlated well with the reduction of angiogenesis induced by myeloma RPMI8226 cells. The present study also showed that ART downregulated the expression of VEGF and Ang-1 in RPMI8226 cells and reduced the activation of extracellular signal-regulated kinase 1 (ERK1) as well. Therefore, ART can block ERK1/2 activation, downregulate VEGF and Ang-1 expression and inhibit angiogenesis induced by human multiple myeloma RPMI8226 cells. Combined with our previous published data, results from the present study indicate that ART possesses potential anti-myeloma effect.
多发性骨髓瘤（MM）至今仍是一种无法治愈的浆细胞疾病；因此，迫切需要新的基于生物学靶点的治疗方法。我们之前的研究表明，抗疟药青蒿琥酯（ART）通过抑制骨髓瘤细胞的增殖和诱导其凋亡，具有抗骨髓瘤作用。本研究评估了 ART 对人骨髓瘤细胞诱导的血管生成的影响，并阐明了其机制。采用人脐静脉内皮细胞（HUVEC）迁移试验、体外纤维蛋白凝胶主动脉发芽和鸡胚绒毛尿囊膜（CAM）新生血管化体内模型，观察 ART 对人骨髓瘤细胞诱导的血管生成的影响。结果表明，ART 可抑制 HUVEC 迁移，即使在较低浓度（3μmol/L，与对照组相比，P<0.01）下，也可有效抑制骨髓瘤 RPMI8226 细胞的血管生成能力，呈剂量依赖性（3-12μmol/L，P<0.05）。酶联免疫吸附试验（ELISA）定量检测条件培养基（CM）中 VEGF 和 Ang-1 的水平。结果证实，3μmol/L 的 ART 可显著降低 RPMI8226 细胞中 VEGF 和 Ang-1 的分泌（P<0.05），这与骨髓瘤 RPMI8226 细胞诱导的血管生成减少相吻合。本研究还表明，ART 下调 RPMI8226 细胞中 VEGF 和 Ang-1 的表达，并减少细胞外信号调节激酶 1（ERK1）的激活。因此，ART 可以阻断 ERK1/2 激活，下调 VEGF 和 Ang-1 的表达，并抑制人多发性骨髓瘤 RPMI8226 细胞诱导的血管生成。结合我们之前发表的数据，本研究结果表明 ART 具有潜在的抗骨髓瘤作用。
