Sulforaphane: a naturally occurring mammary carcinoma mitotic inhibitor, which disrupts tubulin polymerization
Sulforaphane: a naturally occurring mammary carcinoma mitotic inhibitor, which disrupts tubulin polymerization
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DOI：
10.1093/carcin/bgg192
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发表时间：
2004-02-01
期刊：
影响因子：
4.7
通讯作者：
Singletary, KW
中科院分区：
文献类型：
--
作者：
Jackson, SJT;Singletary, KW
萝卜硫素（SUL），一种在花椰菜和其他十字花科蔬菜中发现的异硫氰酸酯，已被证明可以诱导II期解毒酶，抑制化学诱导的大鼠乳腺肿瘤，最近还可以诱导结肠癌细胞的细胞周期停滞和细胞凋亡。在这里，我们提供的证据表明，SUL也作为乳腺癌抗增殖剂。用浓度高达15 μ M的SUL处理BALB/c小鼠乳腺癌细胞系F3 II，并检查细胞周期停滞和凋亡的标志物。用15 μ M SUL处理异步F3 II细胞导致G（2）/M细胞周期停滞，p34（cdc 2）（cdc 2）激酶活性升高，Bcl-2下调，半胱天冬酶激活的证据，以及浓缩的核染色质聚集。随后将同步化细胞暴露于15 μ M SUL，导致前期/前中期有丝分裂像数目增加，表明细胞周期进展超过G（2），并在有丝分裂早期停滞。此外，15 μ M SUL处理的细胞显示异常的有丝分裂纺锤体，更高剂量的SUL抑制微管蛋白聚合在体外。此外，BALB/c小鼠皮下注射用F3 II细胞处理，随后每天静脉注射SUL（15 nmol/天，持续13天）的小鼠，与赋形剂处理的对照组相比，产生了显著更小的肿瘤（质量减少60%）。肿瘤蛋白质的Western印迹分析表明，在给予SUL的动物样品中，PCNA显著降低（P < 0.05），PARP片段化升高。总之，这些结果表明，SUL在细胞培养物和整个动物中均具有乳腺癌抑制作用。乳腺癌发生的抑制似乎部分涉及有丝分裂微管的扰动和早期M期阻滞与cdc 2激酶激活，表明细胞逮捕前中期退出。
Sulforaphane (SUL), an isothiocyanate found in broccoli and other cruciferous vegetables, has been shown to induce phase II detoxification enzymes, inhibit chemically induced mammary tumors in rats, and more recently to induce cell cycle arrest and apoptosis in cancer cells of the colon. Here, we provide evidence that SUL also acts as a breast cancer anti-proliferative agent. The BALB/c mouse mammary carcinoma cell line F3II was treated with SUL at concentrations up to 15 muM and examined for markers of cell cycle arrest and apoptosis. Treatment of asynchronous F3II cells with 15 muM SUL resulted in G(2)/M cell cycle arrest, elevated p34(cdc2) (cdc2) kinase activity, Bcl-2 down-regulation, evidence of caspase activation, and aggregation of condensed nuclear chromatin. Subsequent exposure of synchronized cells to 15 muM SUL resulted in elevated numbers of prophase/prometaphase mitotic figures, indicating cell cycle progression beyond G(2) and arrest early within mitosis. Moreover, cells treated with 15 muM SUL displayed aberrant mitotic spindles, and higher doses of SUL inhibited tubulin polymerization in vitro. In addition, BALB/c mice injected s.c. with F3II cells and subsequently injected daily i.v. with SUL (15 nmol/day for 13 days) developed significantly smaller tumors (similar to60% less in mass) than vehicle-treated controls. Western blot analysis of tumor proteins demonstrated significantly (P < 0.05) reduced PCNA and elevated PARP fragmentation in samples from animals dosed with SUL. Taken together, these results indicate that SUL has mammary cancer suppressive actions both in cell culture and in the whole animal. Inhibition of mammary carcinogenesis appears in part to involve perturbation of mitotic microtubules and early M-phase block associated with cdc2 kinase activation, indicating that cells arrest prior to metaphase exit.