2-methoxyestradiol induces interferon gene expression and apoptosis in osteosarcoma cells
2-methoxyestradiol induces interferon gene expression and apoptosis in osteosarcoma cells
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DOI：
10.1016/s8756-3282(01)00681-0
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发表时间：
2002-02-01
期刊：
影响因子：
4.1
通讯作者：
Turner, RT
中科院分区：
文献类型：
--
作者：
Maran, A;Zhang, M;Turner, RT
2-甲氧基yestradiol （2-ME）是17β -雌二醇的天然代谢物，被认为是肿瘤细胞增殖的生理抑制剂。本研究探讨了2-ME对体外培养骨肉瘤细胞的影响。在暴露于2-ME的MG63和TE85人骨肉瘤细胞中观察到剂量依赖性生长抑制。2-ME对细胞的杀伤是配体特异性的；直接前体（2-羟基雌二醇）、母体化合物（17 - β -雌二醇）和雌酮的等效代谢物（2-甲氧基雌酮）的效力和疗效较差。此外，2-ME在杀伤具有或不具有雌激素受体- α和- β的永生化人胎儿成骨细胞（hFOB）和大鼠骨肉瘤细胞方面同样有效（ROS17/2.8）。2-ME对转化和永生化的成骨细胞具有选择性的细胞毒性；2- me （2 mum）对人成骨细胞原代培养增殖无影响。与强效雌激素受体配体ici - 182780共同治疗，并没有减少2- me诱导的骨肉瘤细胞死亡，这意味着这种作用不是由传统的雌激素受体介导的。2-ME处理后，骨基质蛋白基因、1型胶原蛋白和骨连接蛋白的表达水平短暂降低，表明存活细胞能够产生骨基质。2- me介导的骨肉瘤细胞杀伤是由于诱导细胞凋亡；治疗诱导干扰素基因在12小时内表达，组织学证据显示2-ME治疗后48小时内细胞凋亡。因此，我们的研究结果表明，2-ME对骨肉瘤细胞具有高度的细胞毒性，而对正常的成骨细胞没有毒性。这些发现表明，进一步研究2-ME作为治疗骨肉瘤的潜在干预措施是有必要的。（骨30:393-398；2002）(C) 2002由爱思唯尔科学公司。版权所有。
2-Methoxyestradiol (2-ME), a naturally occurring mammalian metabolite of 17beta-estradiol, has been implicated as a physiological inhibitor of tumor cell proliferation. In this study, the effects of 2-ME on cultured osteosarcomatous cells were investigated. Dose-dependent growth inhibition was observed in MG63 and TE85 human osteosarcoma cells exposed to 2-ME. The cell killing by 2-ME was ligand-specific; the immediate precursor (2-hydroxyestradiol), the parent compound (17beta-estradiol), and the equivalent metabolite of estrone (2-methoxyestrone) exhibited less potency and efficacy. Furthermore, 2-ME was similarly effective at killing immortalized human fetal osteoblastic cells (hFOB) with and without estrogen receptor-alpha and -beta and rat osteosarcoma cells (ROS17/2.8). The cytotoxicity of 2-ME was selective to transformed and immortalized ostcoblastic cells; 2-ME (2 mum) had no effect on the proliferation of primary cultures of human osteoblasts. Co-treatment with the potent estrogen receptor ligand, ICI-182,780, did not reduce 2-ME-induced osteosarcoma cell death, implying that this action is not mediated by conventional estrogen receptors. The expression levels of bone matrix protein genes, type 1 collagen and osteonectin, were transiently reduced after 2-ME treatment, suggesting that the surviving cells are capable of producing bone matrix. The 2-ME-mediated killing of osteosarcoma cells was due to the induction of apoptosis; treatment induced expression of interferon genes within 12 h and histological evidence of apoptosis within 48 h of 2-ME treatment. Thus, our results demonstrate that 2-ME is highly cytotoxic to osteosarcoma cells but not normal osteoblasts. These findings suggest that further study of 2-ME as a potential intervention for treatment of osteosarcoma is warranted. (Bone 30: 393-398; 2002) (C) 2002 by Elsevier Science Inc. All rights reserved.