Oridonin, a diterpenoid purified from Rabdosia rubescens, inhibits the proliferation of cells from lymphoid malignancies in association with blockade of the NF-κB signal pathways
Oridonin, a diterpenoid purified from Rabdosia rubescens, inhibits the proliferation of cells from lymphoid malignancies in association with blockade of the NF-κB signal pathways
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DOI：
10.1158/1535-7163.mct-04-0277
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发表时间：
2005-04-01
影响因子：
5.7
通讯作者：
Taguchi, H
中科院分区：
文献类型：
--
作者：
Ikezoe, T;Yang, Y;Taguchi, H
这项研究发现冬凌草甲素是一种从冬凌草中纯化的天然二萜化合物，可抑制多发性骨髓瘤（MM；U266，RPMI8226）、急性淋巴细胞T细胞白血病（Jurkat）和成人T细胞白血病（MT-1）细胞的生长，其有效剂量可抑制50%的靶细胞（ED50），范围为0.75至 2.7微克/毫升。末端脱氧核苷酸转移酶介导的 dUTP 缺口末端标记染色显示冬凌草甲素以时间依赖性方式引起 MT-1 细胞凋亡。我们探讨了冬凌草甲素对抗凋亡 Bcl-2 家族成员的影响，发现它下调了 MT-1 和 RPMI8226 细胞中 Mcl-1 和 BCL-x(L) 的水平，但不下调 Bcl-2 蛋白的水平。进一步的研究发现，通过荧光素酶报告基因、ELISA 和电泳迁移率变动测定法测量，冬凌草甲素可抑制这些细胞中的核因子 kappa B (NF-kappa B) DNA 结合活性。 Oridonin 还可阻断 Jurkat 细胞以及 RAW264.7 小鼠巨噬细胞中肿瘤坏死因子-α 和脂多糖刺激的 NF-κ B 活性。值得注意的是，冬凌草甲素可降低患者体内新鲜分离的成人 T 细胞白血病（三个样品）、急性淋巴细胞白血病（一个样品）、慢性淋巴细胞白血病（一个样品）、非霍奇金淋巴瘤（三个样品）和 MM（四个样品）细胞的存活率，这与抑制 NF-κ B DNA 结合活性有关。另一方面，冬凌草甲素并不影响健康志愿者正常淋巴细胞的存活。总而言之，冬凌草甲素可能可用作淋巴恶性肿瘤患者的辅助治疗，包括致命性疾病成人 T 细胞白血病。
This study found that oridonin, a natural diterpenoid purified from Rabdosia rubescens, inhibited growth of multiple myeloma (MM; U266, RPMI8226), acute lymphoblastic T-cell leukemia (Jurkat), and adult T-cell leukemia (MT-1) cells with an effective dose that inhibited 50% of target cells (ED50) ranging from 0.75 to 2.7 mu g/mL. Terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling staining showed that oridonin caused apoptosis of MT-1 cells in a time-dependent manner. We explored effects of oridonin on antiapoptotic Bcl-2 family members and found that it down-regulated levels of Mcl-1 and BCL-x(L), but not Bcl-2 protein, in,both MT-1 and RPMI8226 cells. Further studies found that oridonin inhibited nuclear factor-kappa B (NF-kappa B) DNA-binding activity in these cells as measured by luciferase reporter gene, ELISA-based, and electrophoretic mobility shift assays. Oridonin also blocked tumor necrosis factor-alpha-and lipopolysaccharide-stimulated NF-kappa B activity in Jurkat cells as well as RAW264.7 murine macrophages. Of note, oridonin decreased survival of freshly isolated adult T-cell leukemia (three samples), acute lymphoblastic leukemia (one sample), chronic lymphocytic leukemia (one sample), non-Hodgkin's lymphoma (three samples), and MM (four samples) cells from patients in association with inhibition of NF-kappa B DNA-binding activity. On the other hand, oridonin did not affect survival of normal lymphoid cells from healthy volunteers. Taken together, oridonin might be useful as adjunctive therapy for individuals with lymphoid malignancies, including the lethal disease adult T-cell leukemia.