Antisense RNA down-regulation of bcl-2 expression in DU145 prostate cancer cells does not diminish the cytostatic effects of G3139 (Oblimersen).
Antisense RNA down-regulation of bcl-2 expression in DU145 prostate cancer cells does not diminish the cytostatic effects of G3139 (Oblimersen).
复制标题
反义 RNA 下调 DU145 前列腺癌细胞中的 bcl-2 表达不会减弱 G3139 (Oblimersen) 的细胞抑制作用。
DOI：
10.1158/1078-0432.ccr-03-0287
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发表时间：
2004
期刊：
影响因子：
--
通讯作者：
Benimetskaya,Luba
中科院分区：
文献类型：
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作者：
Raffo,Anthony;Lai,JohnathanC;Stein,CA;Miller,Paul;Scaringe,Steven;Khvorova,Anastasia;Benimetskaya,Luba
目的：抑制bcl2蛋白的功能被认为可以使细胞对细胞毒性化疗敏感，从而为研究治疗提供了一个有吸引力的靶点。G3139是一种针对bcl2mRNA起始密码子区域的硫代反义寡核苷酸，目前正在几个第二阶段和第三阶段临床试验中进行评估。然而，这种分子的作用机制似乎依赖于反义和非反义事件的组合。实验设计：在这项工作中，我们通过两种不同的反义RNA策略(反义RNA和小干扰RNA)将BCL-2蛋白的表达下调了80%-90%。结果：即使通过这两种策略中的任何一种策略下调BCL-2蛋白的表达，G3139诱导的细胞表型(抑制细胞生长和产生活性氧)与模拟感染或野生型DU145细胞基本相同。结论：BCL-2在DU145细胞中的表达与长寿表型无明显相关性，G3139在DU145细胞中产生细胞抑制作用的机制不依赖于BCL-2。
Purpose:Inhibition of the function of the bcl-2 protein has been postulated to sensitize cells to cytotoxic chemotherapy, and thus provides an attractive target for investigative therapies. G3139, a phosphorothioate antisense oligonucleotide targeted to the initiation codon region of the bcl-2 mRNA, is currently being evaluated in several Phase II and Phase III clinical trials. However, the mechanism of action of this molecule appears to depend on a combination of antisense plus nonantisense events. Indeed, the very idea that bcl-2 is a critical target is, at least in part, an extrapolation from experiments in which intracellular bcl-2 protein concentrations have been dramatically increased, yielding chemoresistant cells.Experimental Design:In this work, we down-regulated the expression of bcl-2 protein by 80–90% by two different antisense RNA strategies (antisense RNA and small interfering RNA) in DU145 prostate cancer cells.Results:Even after down-regulation of bcl-2 protein expression by either one of these strategies, the cellular phenotype induced by subsequent G3139 treatment (inhibition of cellular growth and the generation of reactive oxygen species) was essentially identical to that induced in mock-infected or wild-type DU145 cells in which bcl-2 protein expression had not been down-regulated previously.Conclusions:These results strongly suggest that bcl-2 expression in DU145 cells is not strongly associated with the prolife phenotype and that the mechanism by which G3139 produces its cytostatic effects in this cell line is bcl-2 independent.