Tannin-Spitz Tehila, Grossman Shlomo, Dovrat Sara, Gottlieb Hugo E, Bergman Margalit
The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel.
Biochem Pharmacol. 2007 Jan 1;73(1):56-67. doi: 10.1016/j.bcp.2006.09.012. Epub 2006 Sep 17.
Our aim was to study the effects of cucurbitacin glucosides extracted from Citrullus colocynthis leaves on human breast cancer cell growth. Leaves were extracted, resulting in the identification of cucurbitacin B/E glucosides. The cucurbitacin glucoside combination (1:1) inhibited growth of ER(+) MCF-7 and ER(-) MDA-MB-231 human breast cancer cell lines. Cell-cycle analysis showed that treatment with isolated cucurbitacin glucoside combination resulted in accumulation of cells at the G(2)/M phase of the cell cycle. Treated cells showed rapid reduction in the level of the key protein complex necessary to the regulation of G(2) exit and initiation of mitosis, namely the p34(CDC2)/cyclin B1 complex. cucurbitacin glucoside treatment also caused changes in the overall cell morphology from an elongated form to a round-shaped cell, which indicates that cucurbitacin treatment caused impairment of actin filament organization. This profound morphological change might also influence intracellular signaling by molecules such as PKB, resulting in inhibition in the transmission of survival signals. Reduction in PKB phosphorylation and inhibition of survivin, an anti-apoptosis family member, was observed. The treatment caused elevation in p-STAT3 and in p21(WAF), proven to be a STAT3 positive target in absence of survival signals. Cucurbitacin glucoside treatment also induced apoptosis, as measured by Annexin V/propidium iodide staining and by changes in mitochondrial membrane potential (DeltaPsi) using a fluorescent dye, JC-1. We suggest that cucurbitacin glucosides exhibit pleiotropic effects on cells, causing both cell cycle arrest and apoptosis. These results suggest that cucurbitacin glucosides might have therapeutic value against breast cancer cells.
我们的目的是研究从苦西瓜叶中提取的葫芦素糖苷对人乳腺癌细胞生长的影响。提取叶片后，鉴定出葫芦素B/E糖苷。葫芦素糖苷组合（1:1）抑制雌激素受体阳性（ER(+)）的MCF-7和雌激素受体阴性（ER(-)）的MDA-MB-231人乳腺癌细胞系的生长。细胞周期分析表明，用分离出的葫芦素糖苷组合处理导致细胞在细胞周期的G(2)/M期积累。处理后的细胞显示，对G(2)期退出和有丝分裂起始起调节作用的关键蛋白复合物，即p34(CDC2)/细胞周期蛋白B1复合物的水平迅速降低。葫芦素糖苷处理还导致细胞整体形态从细长形变为圆形，这表明葫芦素处理导致肌动蛋白丝组织受损。这种深刻的形态变化也可能影响诸如蛋白激酶B（PKB）等分子的细胞内信号传导，从而导致生存信号传递受到抑制。观察到PKB磷酸化减少以及抗凋亡家族成员生存素受到抑制。该处理导致p-STAT3和p21(WAF)升高，在没有生存信号的情况下，p21(WAF)被证明是STAT3的阳性靶点。通过膜联蛋白V/碘化丙啶染色以及使用荧光染料JC-1检测线粒体膜电位（ΔΨ）的变化来测定，葫芦素糖苷处理也诱导了细胞凋亡。我们认为葫芦素糖苷对细胞具有多效性作用，导致细胞周期停滞和细胞凋亡。这些结果表明葫芦素糖苷可能对乳腺癌细胞具有治疗价值。
