Columbamine suppresses the proliferation and neovascularization of metastatic osteosarcoma U2OS cells with low cytotoxicity
Columbamine suppresses the proliferation and neovascularization of metastatic osteosarcoma U2OS cells with low cytotoxicity
复制标题
鸽胺抑制转移性骨肉瘤 U2OS 细胞的增殖和新生血管形成，且细胞毒性低
DOI：
10.1016/j.toxlet.2012.10.015
复制
发表时间：
2012-12-17
影响因子：
3.5
通讯作者：
Zhou, Quansheng
中科院分区：
文献类型：
--
作者：
Bao, Meimei;Cao, Zhifei;Zhou, Quansheng
骨肉瘤是儿童和青少年最常见的恶性骨肿瘤之一。尽管近几十年来人们在抗骨肉瘤治疗方面做出了广泛的努力，但仍然没有有效的低毒性药物来治疗转移性骨肉瘤患者。因此，非常需要有效的抗转移性骨肉瘤药物。在这项研究中，我们探索新的小分子抗转移骨肉瘤药物，并发现Columbamine（COL），中药黄连的活性成分，抑制骨肉瘤U2 OS细胞的增殖和新生血管。COL在体外有效抑制U2 OS细胞增殖，IC 50为21.31 +/- 0.38 μ M，具有低细胞毒性。机制研究表明，COL诱导细胞周期停滞在G2/M转换，这与减弱CDK 6基因表达和减少STAT 3磷酸化有关。COL在任何测试剂量下均未显著促进U2 OS细胞凋亡。此外，COL抑制U2 OS细胞介导的新生血管形成，这是伴随着下调基质金属蛋白酶（MMP）2的表达和减少细胞迁移，粘附和侵袭。综上所述，我们的数据表明COL对转移性人骨肉瘤U2 OS细胞具有低毒性的抗增殖和抗血管生成作用。这些结果保证COL作为潜在的抗骨肉瘤和抗癌药物的进一步研究。(C)2012爱思唯尔爱尔兰有限公司保留所有权利。
Osteosarcoma is one of the most common malignant bone tumors in children and adolescents. Although extensive efforts have been made in anti-osteosarcoma therapy in recent decades, there are no effective low-toxicity drugs for treating patients with metastatic osteosarcoma. Hence, potent anti-metastatic osteosarcoma drugs are highly desired. In this study, we explored novel small molecular anti-metastatic osteosarcoma agents and found that columbamine (COL), an active component of the herb Coptis chinensis, inhibited the proliferation and neovascularization of metastatic osteosarcoma U2OS cells. COL effectively suppressed U2OS cell proliferation in vitro with an IC50 of 21.31 +/- 0.38 mu M, with low cytotoxicity. Mechanistic studies revealed that COL induces cell cycle arrest at the G2/M transition, which is associated with attenuating CDK6 gene expression and diminishing STAT3 phosphorylation. COL did not significantly promote U2OS cell apoptosis at any of the dosages tested. Additionally, COL inhibited U2OS cell-mediated neovascularization, which was accompanied by the down-regulation of matrix metalloproteinase (MMP) 2 expression and reduction of cell migration, adhesion, and invasion. Taken together, our data show that COL exerts anti-proliferative and anti-vasculogenic effects on metastatic human osteosarcoma U2OS cells with low toxicity. These results warrant further investigation of COL as a potential anti-osteosarcoma and anti-cancer drug. (C) 2012 Elsevier Ireland Ltd. All rights reserved.