2-methoxyestradiol up-regulates death receptor 5 and induces apoptosis through activation of the extrinsic pathway.
2-methoxyestradiol up-regulates death receptor 5 and induces apoptosis through activation of the extrinsic pathway.
复制标题
2-methoxyestradiol 上调死亡受体 5 并通过激活外源途径诱导细胞凋亡。
作者：
T. Lavallee;Xiaoguo H. Zhan;Michelle S. Johnson;Chris J Herbstritt;G. Swartz;Mark S Williams;Wendy A Hembrough;S. Green;V. Pribluda
2-甲氧基雌二醇（2 ME 2）是雌二醇的天然代谢产物，是一种有效的抗肿瘤和抗血管生成剂。在体外，2 ME 2抑制多种细胞系和原代培养物的增殖，并且在许多体内模型中，它已被证明是肿瘤生长和血管生成的有效抑制剂。2 ME 2目前正在进行多项I期和II期临床试验，名称为Panzem。尽管已经提出了该化合物的各种分子靶点，但2 ME 2发挥其作用的机制仍然不确定。这项研究表明，2 ME 2使用外源性途径诱导细胞凋亡。2 ME 2处理导致死亡受体5（DR 5）蛋白在体外和体内表达上调，并使细胞对DR 5配体肿瘤坏死因子相关凋亡诱导配体（TRAIL）的细胞毒性活性更敏感。2 ME 2诱导的细胞凋亡需要半胱天冬酶激活，动力学研究表明半胱天冬酶-8、半胱天冬酶-9和半胱天冬酶-3依次激活。通过显性负性Fas相关死亡结构域的表达阻断死亡受体信号传导严重减弱2 ME 2诱导细胞凋亡的能力。由于2 ME 2给药在临床上没有表现出剂量限制性毒性，因此DR 5表达可作为生物学反应的替代标志物。
2-Methoxyestradiol (2ME2), a natural metabolite of estradiol, is a potent antitumor and antiangiogenic agent. In vitro, 2ME2 inhibits the proliferation of a wide variety of cell lines and primary cultures, and in numerous models in vivo, it has been shown to be an effective inhibitor of tumor growth and angiogenesis. 2ME2 is currently in several Phase I and Phase II clinical trials under the name Panzem. Although various molecular targets have been proposed for this compound, the mechanism by which 2ME2 exerts its effects is still uncertain. This study shows that 2ME2 uses the extrinsic pathway for induction of apoptosis. 2ME2 treatment results in up-regulation of death receptor 5 (DR5) protein expression in vitro and in vivo and renders cells more sensitive to the cytotoxic activities of the DR5 ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). 2ME2-induced apoptosis requires caspase activation and kinetic studies show the sequential activation of caspase-8, caspase-9, and caspase-3. Blockage of death receptor signaling by expression of dominant-negative Fas-associated death domain severely attenuates the ability of 2ME2 to induce apoptosis. Because 2ME2 administration has not manifested dose-limiting toxicity in the clinic, DR5 expression may serve as a surrogate marker for biological response.
DOI：
10.2174/1566524013364239
发表时间：
2001-03-01
期刊：
Current Molecular Medicine (Hilversum)
影响因子：
--
作者：
Olson, M.;Kornbluth, S.
通讯作者：
Kornbluth, S.