Mohan Renu, Panda Dulal
School of Biosciences and Bioengineering, Indian Institute of Technology, Bombay, Mumbai, India.
Cancer Res. 2008 Aug 1;68(15):6181-9. doi: 10.1158/0008-5472.CAN-08-0584.
Estramustine (EM) alone or in combination with other anticancer agents is clinically used for the treatment of hormone refractory prostate cancer. Furthermore, EM has been shown to potently inhibit the proliferation of different types of cancer cells in culture apparently by targeting microtubules; however, the antiproliferative mechanism of action of EM is not clear. In this work, we have shown that EM strongly suppressed the dynamic instability of individual microtubules in MCF-7 cells by reducing the rates of growing and shortening excursions and increasing the time microtubule spent in the pause state. At its half maximal proliferation inhibitory concentration (IC(50)), EM exerted strong suppressive effects on the dynamics of microtubules in MCF-7 cells without detectably affecting either the organization or the polymerized mass of microtubules. At relatively high concentrations (5 x IC(50)), EM significantly depolymerized microtubules in the cells. Furthermore, the microtubules were found highly acetylated, supporting the conclusion that they were stabilized by the drug. EM treatment induced spindle abnormalities in MCF-7 cells, and a major population of the arrested mitotic cells was multipolar. EM also perturbed the microtubule-kinetochore interaction, thereby activating the spindle assembly checkpoint and leading to apoptotic cell death.
雌莫司汀（EM）单独使用或与其他抗癌药物联合使用在临床上用于治疗激素难治性前列腺癌。此外，已表明EM明显通过靶向微管在培养物中有效抑制不同类型癌细胞的增殖；然而，EM的抗增殖作用机制尚不清楚。在这项研究中，我们表明EM通过降低微管生长和缩短的速率并增加微管在暂停状态下花费的时间，强烈抑制MCF-7细胞中单个微管的动态不稳定性。在其半数最大增殖抑制浓度（IC50）时，EM对MCF-7细胞中微管的动态有强烈的抑制作用，而未检测到对微管的组织或聚合质量有影响。在相对高浓度（5×IC50）时，EM使细胞中的微管显著解聚。此外发现微管高度乙酰化，支持它们被药物稳定的结论。EM处理诱导MCF-7细胞中的纺锤体异常，并且大部分停滞的有丝分裂细胞是多极的。EM还扰乱微管-动粒相互作用，从而激活纺锤体组装检查点并导致凋亡性细胞死亡。
