INRS-Institut Armand-Frappier , Laval, QC , Canada.
PeerJ. 2013 Aug 8;1:e122. doi: 10.7717/peerj.122. Print 2013.
Prostate cancer is a prevalent age-related disease in North America, accounting for about 15% of all diagnosed cancers. We have previously identified lithocholic acid (LCA) as a potential chemotherapeutic compound that selectively kills neuroblastoma cells while sparing normal human neurons. Now, we report that LCA inhibits the proliferation of androgen-dependent (AD) LNCaP prostate cancer cells and that LCA is the most potent bile acid with respect to inducing apoptosis in LNCaP as well as androgen-independent (AI) PC-3 cells, without killing RWPE-1 immortalized normal prostate epithelial cells. In LNCaP and PC-3 cells, LCA triggered the extrinsic pathway of apoptosis and cell death induced by LCA was partially dependent on the activation of caspase-8 and -3. Moreover, LCA increased cleavage of Bid and Bax, down-regulation of Bcl-2, permeabilization of the mitochondrial outer membrane and activation of caspase-9. The cytotoxic actions of LCA occurred despite the inability of this bile acid to enter the prostate cancer cells with about 98% of the nominal test concentrations present in the extracellular culture medium. With our findings, we provide evidence to support a mechanism of action underlying the broad anticancer activity of LCA in various human tissues.
前列腺癌是北美一种常见的与年龄相关的疾病，约占所有诊断癌症的 15%。我们之前已经确定石胆酸（LCA）是一种潜在的化疗化合物，它可以选择性地杀死神经母细胞瘤细胞，而不伤害正常的人类神经元。现在，我们报告 LCA 抑制雄激素依赖性（AD）LNCaP 前列腺癌细胞的增殖，并且 LCA 是在诱导 LNCaP 以及雄激素非依赖性（AI）PC-3 细胞凋亡方面最有效的胆汁酸，而不会杀死 RWPE-1 永生化正常前列腺上皮细胞。在 LNCaP 和 PC-3 细胞中，LCA 触发了细胞凋亡的外在途径，LCA 诱导的细胞死亡部分依赖于半胱天冬酶-8 和 -3 的激活。此外，LCA 增加了 Bid 和 Bax 的裂解，Bcl-2 的下调，线粒体外膜的通透性以及 caspase-9 的激活。尽管这种胆汁酸无法进入前列腺癌细胞，但仍存在约 98%的名义测试浓度存在于细胞外培养基中，LCA 的细胞毒性作用仍在发生。有了我们的发现，我们提供了证据来支持 LCA 在各种人类组织中具有广泛抗癌活性的作用机制。
