Pledgie-Tracy Allison, Sobolewski Michele D, Davidson Nancy E
The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, 1550 Orleans Street, Baltimore, MD 21231, USA.
Mol Cancer Ther. 2007 Mar;6(3):1013-21. doi: 10.1158/1535-7163.MCT-06-0494. Epub 2007 Mar 5.
Sulforaphane, an isothiocyanate found in cruciferous vegetables, has been shown to induce phase 2 detoxication enzymes and inhibit the growth of chemically induced mammary tumors in rats, although the exact mechanisms of action of sulforaphane are not understood. In this study, we evaluated the effects of sulforaphane on cell growth and death in several human breast cancer cell lines and examined the hypothesis that sulforaphane acts as a histone deacetylase (HDAC) inhibitor in these cell lines. Sulforaphane treatment inhibited cell growth, induced a G(2)-M cell cycle block, increased expression of cyclin B1, and induced oligonucleosomal DNA fragmentation in the four human breast cancer cell lines examined, MDA-MB-231, MDA-MB-468, MCF-7, and T47D cells. Activation of apoptosis by sulforaphane in MDA-MB-231 cells seemed to be initiated through induction of Fas ligand, which resulted in activation of caspase-8, caspase-3, and poly(ADP-ribose) polymerase, whereas apoptosis in the other breast cancer cell lines was initiated by decreased Bcl-2 expression, release of cytochrome c into the cytosol, activation of caspase-9 and caspase-3, but not caspase-8, and poly(ADP-ribose) polymerase cleavage. Sulforaphane inhibited HDAC activity and decreased the expression of estrogen receptor-alpha, epidermal growth factor receptor, and human epidermal growth factor receptor-2 in each cell line, although no change in the acetylation of H3 or H4 was seen. These data suggest that sulforaphane inhibits cell growth, activates apoptosis, inhibits HDAC activity, and decreases the expression of key proteins involved in breast cancer proliferation in human breast cancer cells. These results support testing sulforaphane in vivo and warrant future studies examining the clinical potential of sulforaphane in human breast cancer.
萝卜硫素是一种存在于十字花科蔬菜中的异硫氰酸盐，已被证明可诱导Ⅱ相解毒酶，并抑制大鼠化学诱导性乳腺肿瘤的生长，尽管萝卜硫素的确切作用机制尚不清楚。在本研究中，我们评估了萝卜硫素对几种人乳腺癌细胞系细胞生长和死亡的影响，并检验了萝卜硫素在这些细胞系中作为组蛋白去乙酰化酶（HDAC）抑制剂发挥作用的假说。在所检测的4种人乳腺癌细胞系MDA-MB-231、MDA-MB-468、MCF-7和T47D细胞中，萝卜硫素处理抑制细胞生长，诱导G(2)-M期细胞周期阻滞，增加细胞周期蛋白B1的表达，并诱导寡核小体DNA片段化。萝卜硫素在MDA-MB-231细胞中诱导凋亡似乎是通过诱导Fas配体启动的，这导致半胱天冬酶-8、半胱天冬酶-3和聚（ADP-核糖）聚合酶的激活，而其他乳腺癌细胞系中的凋亡是由Bcl-2表达降低、细胞色素c释放到细胞质中、半胱天冬酶-9和半胱天冬酶-3激活，但不是半胱天冬酶-8激活以及聚（ADP-核糖）聚合酶裂解启动的。萝卜硫素抑制HDAC活性，并降低每个细胞系中雌激素受体-α、表皮生长因子受体和人表皮生长因子受体-2的表达，尽管未观察到H3或H4乙酰化的变化。这些数据表明，萝卜硫素抑制人乳腺癌细胞的细胞生长，激活凋亡，抑制HDAC活性，并降低参与乳腺癌增殖的关键蛋白的表达。这些结果支持在体内测试萝卜硫素，并保证未来研究检验萝卜硫素在人乳腺癌中的临床潜力。
