A novel anticancer agent, retigeric acid B, displays proliferation inhibition, S phase arrest and apoptosis activation in human prostate cancer cells
A novel anticancer agent, retigeric acid B, displays proliferation inhibition, S phase arrest and apoptosis activation in human prostate cancer cells
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一种新型抗癌剂维替格酸 B 在人前列腺癌细胞中表现出增殖抑制、S 期阻滞和细胞凋亡激活作用
DOI：
10.1016/j.cbi.2010.07.024
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发表时间：
2010-12-05
影响因子：
5.1
通讯作者：
Lou, Hong-xiang
中科院分区：
文献类型：
--
作者：
Liu, Han;Liu, Yi-qing;Lou, Hong-xiang
Retigeric Acid B (RB) 是一种天然存在的五环三萜酸，因其体外抗真菌特性而闻名。在这里，我们观察到 RB 以剂量依赖性方式抑制前列腺癌细胞增殖并诱导细胞死亡，但对非癌性前列腺上皮细胞活力的抑制作用非常小。用RB处理雄激素非依赖性PC-3细胞引起p21(Cip1)适度增加，并强制细胞周期停滞在S期。 S期阻断伴随着细胞周期蛋白B的减少，以及细胞周期蛋白E和细胞周期蛋白A蛋白以及磷酸化视网膜母细胞瘤蛋白（pRb）的增加，而暴露于RB的PC-3细胞中cdk2的表达几乎保持不变。此外，RB 显着抑制 DNA 合成，以剂量依赖性方式减少 BrdU 掺入 DNA，并通过诱导更高比例的 Bax/Bcl-2 蛋白和激活 caspase-3 来增强 PC-3 细胞的凋亡，从而促进聚（ADP-核糖）聚合酶（PARP）的裂解。然而，用泛 caspase 抑制剂 z-VAD-fmk 预处理仅部分减轻了 PC-3 细胞中 RB 触发的细胞凋亡，表明 caspase 依赖性和 caspase 独立途径都参与其中。此外，用RB处理雄激素敏感的LNCaP细胞会导致雄激素受体（AR）表达减少，并随后降低AR的反式活性。这些观察结果有助于支持寻找有希望的治疗前列腺癌的候选药物。 (C) 2010 Elsevier Ireland Ltd. 保留所有权利。
Retigeric acid B (RB), a naturally occurring pentacyclic triterpenic acid, has been noted for its antifungal properties in vitro. Here, we observed that RB inhibited prostate cancer cell proliferation and induced cell death in a dose-dependent manner, but exerted very little inhibitory effect on noncancerous prostate epithelial cell viability. Treatment of androgen-independent PC-3 cells with RB caused a moderate increase in p21(Cip1), and enforced the cell cycle arrest in the S phase. A block of S phase was accompanied with decreases in cyclin B, and increases in cyclin E and cyclin A proteins and phosphorylated retinoblastoma protein (pRb), whereas the expression of cdk2 remained almost unchanged in PC-3 cells exposed to RB. Moreover, RB significantly inhibited DNA synthesis with a dose-dependent reduction in the incorporation of BrdU into DNA, and enhanced apoptosis of PC-3 cells with induction of a higher ratio of Bax/Bcl-2 proteins, and activation of caspase-3 which, in turn, promoted the cleavage of poly (ADP-ribose) polymerase (PARP). However, pretreatment with the pan-caspase inhibitor z-VAD-fmk only partially alleviated RB-triggered apoptosis in PC-3 cells, suggesting the involvement of both caspase-dependent and caspase-independent pathways. Additionally, treatment of androgen-sensitive LNCaP cells with RB led to a reduction in the expression of androgen receptor (AR), and subsequently decreased the transactivity of AR. These observations help to support the search for promising candidates to treat prostate cancer. (C) 2010 Elsevier Ireland Ltd. All rights reserved.