Drug-induced apoptosis is not necessarily dependent on macromolecular synthesis or proliferation in the p53-negative human prostate cancer cell line PC-3.
Drug-induced apoptosis is not necessarily dependent on macromolecular synthesis or proliferation in the p53-negative human prostate cancer cell line PC-3.
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发表时间：
1995-05
期刊：
影响因子：
11.2
通讯作者：
M. Borner;C. Myers;Oliver Sartor;Y. Sei;T. Toko;J. Trepel;E. Schneider
中科院分区：
文献类型：
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作者：
M. Borner;C. Myers;Oliver Sartor;Y. Sei;T. Toko;J. Trepel;E. Schneider
细胞发生凋亡的倾向被认为是化疗敏感性的决定因素，不直接依赖于特定的药物-靶标相互作用。雄激素非依赖型前列腺癌通常对细胞毒性药物难治，我们测试了这是否是由于细胞凋亡能力的丧失。将激素不敏感和p53阴性的人前列腺癌细胞PC-3暴露于22 μ m顺铂、1 μ m喜树碱、10 μ m tenoposide、135 μ m长春新碱或10 μ m洛伐他汀72小时，可导致细胞死亡、核小体间DNA断裂和典型的细胞凋亡形态学改变。1 μ m环己亚胺可阻止抗癌药物诱导的细胞凋亡，而高浓度（1mm）环己亚胺可诱导细胞凋亡，说明细胞凋亡不需要蛋白质合成。由于环己亚胺影响了PC-3细胞的DNA合成和增殖，我们测试了DNA聚合酶抑制剂aphidicolin是否也能抑制药物诱导的细胞凋亡。与环己亚胺相比，阿菲迪克林仅抑制长春新碱诱导的细胞凋亡。环己亚胺阻止了药物引起的细胞周期分布的变化，除了新碱，而阿菲迪克林导致细胞在G1-S边界的积累，与所使用的药物无关。这些数据表明，在这个系统中，大分子合成、活跃的细胞循环和p53表达并不是细胞凋亡进行的必要条件。
The propensity of a cell to undergo apoptosis has been proposed to be a determinant for chemotherapy sensitivity that is not directly dependent on specific drug-target interactions. Androgen-independent prostate cancer is typically refractory to cytotoxic drugs, and we tested whether this is due to a loss of the ability to undergo apoptosis. Exposure of the hormone-insensitive and p53-negative human prostate carcinoma cell line PC-3 to 22 microM cisplatin, 1 microM camptothecin, 10 microM tenoposide, 135 nM vincristine, or 10 microM lovastatin for 72 h caused cell death, internucleosomal DNA fragmentation, and morphological changes typical for apoptosis. One microM cycloheximide prevented anticancer drug-induced apoptosis, whereas high concentration (1 mM) of cycloheximide alone induced apoptosis, indicating that protein synthesis was not needed for these cells to undergo apoptosis. Since cycloheximide affected DNA synthesis and proliferation of PC-3 cells, we tested whether the DNA polymerase inhibitor aphidicolin could also suppress drug-induced apoptosis. In contrast to cycloheximide, aphidicolin inhibited only vincristine-induced apoptosis. Cycloheximide prevented drug-induced changes in cell cycle distribution except for vincristine, while aphidicolin led to an accumulation of cells at the G1-S border independent of the drug used. These data indicate that macromolecular synthesis, active cell cycling, and p53 expression are not required for apoptosis to proceed in this system.