Mantena Sudheer K, Sharma Som D, Katiyar Santosh K
Department of Dermatology, University of Alabama at Birmingham, Volker Hall 557, 1670 University Boulevard, P.O. Box 202, Birmingham, AL 35294, USA.
Mol Cancer Ther. 2006 Feb;5(2):296-308. doi: 10.1158/1535-7163.MCT-05-0448.
Berberine, a naturally occurring isoquinoline alkaloid, has been shown to possess anti-inflammatory and antitumor properties in some in vitro systems. Here, we report that in vitro treatment of androgen-insensitive (DU145 and PC-3) and androgen-sensitive (LNCaP) prostate cancer cells with berberine inhibited cell proliferation and induced cell death in a dose-dependent (10-100 micromol/L) and time-dependent (24-72 hours) manner. Treatment of nonneoplastic human prostate epithelial cells (PWR-1E) with berberine under identical conditions did not significantly affect their viability. The berberine-induced inhibition of proliferation of DU145, PC-3, and LNCaP cells was associated with G1-phase arrest, which in DU145 cells was associated with inhibition of expression of cyclins D1, D2, and E and cyclin-dependent kinase (Cdk) 2, Cdk4, and Cdk6 proteins, increased expression of the Cdk inhibitory proteins (Cip1/p21 and Kip1/p27), and enhanced binding of Cdk inhibitors to Cdk. Berberine also significantly (P < 0.05-0.001) enhanced apoptosis of DU145 and LNCaP cells with induction of a higher ratio of Bax/Bcl-2 proteins, disruption of mitochondrial membrane potential, and activation of caspase-9, caspase-3, and poly(ADP-ribose) polymerase. Pretreatment with the pan-caspase inhibitor z-VAD-fmk partially, but significantly, blocked the berberine-induced apoptosis, as also confirmed by the comet assay analysis of DNA fragmentation, suggesting that berberine-induced apoptosis of human prostate cancer cells is mediated primarily through the caspase-dependent pathway. The effectiveness of berberine in checking the growth of androgen-insensitive, as well as androgen-sensitive, prostate cancer cells without affecting the growth of normal prostate epithelial cells indicates that it may be a promising candidate for prostate cancer therapy.
小檗碱是一种天然存在的异喹啉生物碱，已在一些体外系统中显示出具有抗炎和抗肿瘤特性。在此，我们报告，用小檗碱在体外处理雄激素不敏感（DU145和PC - 3）及雄激素敏感（LNCaP）前列腺癌细胞，可抑制细胞增殖并诱导细胞死亡，呈剂量依赖性（10 - 100微摩尔/升）和时间依赖性（24 - 72小时）。在相同条件下用小檗碱处理非肿瘤性人前列腺上皮细胞（PWR - 1E），对其活力无显著影响。小檗碱诱导的DU145、PC - 3和LNCaP细胞增殖抑制与G1期阻滞相关，在DU145细胞中，这与细胞周期蛋白D1、D2和E以及细胞周期蛋白依赖性激酶（Cdk）2、Cdk4和Cdk6蛋白表达的抑制、Cdk抑制蛋白（Cip1/p21和Kip1/p27）表达的增加以及Cdk抑制剂与Cdk结合的增强有关。小檗碱还显著（P < 0.05 - 0.001）增强了DU145和LNCaP细胞的凋亡，诱导了更高比例的Bax/Bcl - 2蛋白，破坏了线粒体膜电位，并激活了半胱天冬酶 - 9、半胱天冬酶 - 3和聚（ADP - 核糖）聚合酶。用泛半胱天冬酶抑制剂z - VAD - fmk预处理可部分但显著地阻断小檗碱诱导的凋亡，DNA片段化的彗星试验分析也证实了这一点，表明小檗碱诱导的人前列腺癌细胞凋亡主要通过半胱天冬酶依赖性途径介导。小檗碱在抑制雄激素不敏感以及雄激素敏感前列腺癌细胞生长的同时不影响正常前列腺上皮细胞的生长，这表明它可能是前列腺癌治疗的一个有前景的候选药物。
