Hsieh Tze-Chen, Wijeratne E Kithsiri, Liang Jing-Yu, Gunatilaka A Leslie, Wu Joseph M
Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA.
Biochem Biophys Res Commun. 2005 Nov 11;337(1):224-31. doi: 10.1016/j.bbrc.2005.09.040.
Ponicidin and oridonin are novel diterpenoids isolated from Rabdosia rubescens. We tested their effects in MCF-7 and MDA-MB-231 cells, as representing low and high invasive breast carcinoma, with normal MCF-10A cells. Clonogenicity and proliferation in MCF-7 cells were inhibited more significantly by ponicidin than oridonin, while the reverse was observed in MCF-10A cells. Ponicidin and oridonin induced S/G2M arrest and G1/S block in MCF-7 cells. In MCF-10A cells treated with either diterpenoid, induction of apoptosis was observed. Moreover, oridonin almost completely blocked MCF-10A progression from S to G2/M phase; in contrast, ponicidin-treated MCF-10A cells showed no discernable changes in cell cycle phase distribution. Neither diterpenoid affected growth of MDA-MB-231 cells, at the dose range effective for MCF-7 or MCF-10A cells. Ponicidin-treated MCF-7 cells expressed reduced levels of cyclin B1, cdc2, transcription factor E2F, and Rb including phosphorylation at S780. Less pronounced effects were found in cells treated with oridonin. Neither compound altered cyclin D1 and cdk4 in MCF-7 cells. In MCF-10A cells, oridonin was more active than ponicidin in inhibiting the expression of cyclin B1, cdc2, S780-phosphorylated Rb, and E2F. To further investigate induction of apoptosis in MCF-10A cells, we measured changes in NF-kappaB. Decreases in p65 or p50 forms of NF-kappaB and its upstream regulator I-kappaB were found in oridonin-treated MCF-10A and not MCF-7 cells. Taken together, these results provide a mechanistic framework for the cellular effects of ponicidin and oridonin in different stage breast cancer cells.
冬凌草甲素和冬凌草素是从冬凌草中分离得到的新型二萜类化合物。我们用它们分别处理了MCF-7和MDA-MB-231细胞（分别代表低侵袭性和高侵袭性乳腺癌细胞）以及正常的MCF-10A细胞，测试其效果。与冬凌草素相比，冬凌草甲素对MCF-7细胞克隆形成能力和增殖的抑制作用更为显著，而在MCF-10A细胞中观察到的结果则相反。冬凌草甲素和冬凌草素可诱导MCF-7细胞发生S/G2M期阻滞和G1/S期阻断。在用这两种二萜类化合物处理的MCF-10A细胞中，均观察到了凋亡诱导现象。此外，冬凌草素几乎完全阻断了MCF-10A细胞从S期向G2/M期的进展；相比之下，用冬凌草甲素处理的MCF-10A细胞在细胞周期阶段分布上未显示出明显变化。在对MCF-7或MCF-10A细胞有效的剂量范围内，这两种二萜类化合物均未影响MDA-MB-231细胞的生长。用冬凌草甲素处理的MCF-7细胞中，细胞周期蛋白B1、细胞周期蛋白依赖性激酶2（cdc2）、转录因子E2F和视网膜母细胞瘤蛋白（Rb）的表达水平降低，包括S780位点的磷酸化水平。在用冬凌草素处理的细胞中观察到的影响则不太明显。这两种化合物均未改变MCF-7细胞中细胞周期蛋白D1和细胞周期蛋白依赖性激酶4（cdk4）的水平。在MCF-10A细胞中，冬凌草素在抑制细胞周期蛋白B1、cdc2、S780磷酸化的Rb和E2F的表达方面比冬凌草甲素更有效。为了进一步研究MCF-10A细胞中的凋亡诱导情况，我们检测了核因子κB（NF-κB）的变化。在经冬凌草素处理的MCF-10A细胞中发现了NF-κB的p65或p50形式及其上游调节因子I-κB的减少，而在MCF-7细胞中未发现这种现象。综上所述，这些结果为冬凌草甲素和冬凌草素对不同阶段乳腺癌细胞的细胞效应提供了一个机制框架。
