Symes Juliane C, Kurin Michael, Fleshner Neil E, Medin Jeffrey A
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Mol Cancer Ther. 2008 Sep;7(9):3018-28. doi: 10.1158/1535-7163.MCT-08-0335.
Therapies for prostate cancer based on Fas (CD95) modulation have been under active development at the preclinical stage using immortalized cell lines. To address clinical applicability, the potential of 11 cultures of primary prostate cancer cells to be killed by Fas-mediated apoptosis was investigated. In addition, the effect of the chemotherapeutic agents mitoxantrone and docetaxel on this killing was determined. Apoptosis was induced in patient-derived, primary prostate cancer cells using effector cells engineered by recombinant lentivirus infection to express Fas ligand (FasL) and measured by 51Cr release assays. All cultured prostate cells were found to undergo Fas-mediated killing; cytotoxicity ranged from 12% to 87% after 6 h. These cells were significantly more sensitive to FasL-mediated killing than PC-3 cells. The basal expression of Fas or the expression of five inhibitors of apoptosis (c-FLIP, survivin, cellular inhibitors of apoptosis protein 1 and 2, and bcl-2) was not found to correlate with susceptibility to Fas-mediated killing. Both mitoxantrone and docetaxel were able to induce Fas receptor expression on primary prostate cancer cells, which translated into a 1.5- to 3-fold enhancement of apoptosis mediated by FasL. Whereas mitoxantrone increased the Fas-induced apoptotic response of all cultured prostate cells tested, docetaxel pretreatment was found to preferentially enhance the killing of bcl-2-expressing cells. These findings show that cultured primary prostate cancer cells are sensitive to Fas-mediated apoptosis. Furthermore, the incidence of apoptosis was found to be improved by combining Fas-mediated therapy with standard chemotherapeutic agents. These findings may have significant implications for prostate cancer therapy.
基于Fas（CD95）调节的前列腺癌治疗方法在临床前阶段一直利用永生化细胞系积极开展研究。为了探讨临床适用性，研究了11种原发性前列腺癌细胞培养物被Fas介导的凋亡杀死的可能性。此外，还确定了化疗药物米托蒽醌和多西他赛对这种杀伤作用的影响。使用经重组慢病毒感染工程改造以表达Fas配体（FasL）的效应细胞，在患者来源的原发性前列腺癌细胞中诱导凋亡，并通过51Cr释放试验进行测定。发现所有培养的前列腺细胞都经历Fas介导的杀伤；6小时后细胞毒性范围为12%至87%。这些细胞对FasL介导的杀伤比PC-3细胞敏感得多。未发现Fas的基础表达或五种凋亡抑制剂（c-FLIP、生存素、细胞凋亡抑制蛋白1和2以及bcl-2）的表达与对Fas介导杀伤的敏感性相关。米托蒽醌和多西他赛都能够诱导原发性前列腺癌细胞上Fas受体的表达，这转化为FasL介导的凋亡增强1.5至3倍。虽然米托蒽醌增加了所有测试的培养前列腺细胞的Fas诱导凋亡反应，但发现多西他赛预处理优先增强对表达bcl-2细胞的杀伤。这些发现表明，培养的原发性前列腺癌细胞对Fas介导的凋亡敏感。此外，发现通过将Fas介导的治疗与标准化疗药物联合使用，凋亡发生率得到改善。这些发现可能对前列腺癌治疗具有重要意义。
