A Novel Combination of Withaferin A and Sulforaphane Inhibits Epigenetic Machinery, Cellular Viability and Induces Apoptosis of Breast Cancer Cells.
A Novel Combination of Withaferin A and Sulforaphane Inhibits Epigenetic Machinery, Cellular Viability and Induces Apoptosis of Breast Cancer Cells.
复制标题
DOI：
10.3390/ijms18051092
复制
发表时间：
2017-05-19
影响因子：
5.6
通讯作者：
Tollefsbol TO
中科院分区：
文献类型：
--
作者：
Royston KJ;Udayakumar N;Lewis K;Tollefsbol TO
由于癌症通常被归类为一种具有重要表观遗传成分的疾病，因此具有调节表观基因组能力的天然化合物成为研究的理想候选者。人类有一个复杂的饮食，这说明需要阐明这些生物活性化合物之间的相互作用机制的组合。来自印度冬樱桃的aferin A （WA）和来自十字花科蔬菜的萝卜硫素（SFN）这两种天然化合物具有多种抗癌作用，一些报道称它们具有调节表观遗传过程的能力。我们的研究首次探讨了低生理可达到浓度的WA和SFN对乳腺癌细胞增殖、组蛋白去乙酰化酶1 （HDAC1）和DNA甲基转移酶（dnmt）的联合影响。在最佳浓度下，对对照细胞无不良反应。在MDA-MB-231和MCF-7细胞中，与单独给药相比，联合用药对MCF-7细胞的细胞活力有协同抑制作用，对细胞凋亡的诱导作用更大。HDAC表达多水平下调。最后，我们测定了这些生物活性化合物对促凋亡BAX和抗凋亡BCL-2的联合作用，发现BCL-2降低，BAX升高。综上所述，我们的研究结果表明，低浓度的WA和SFN组合能够促进人类乳腺癌细胞的癌细胞死亡，并调节关键的表观遗传修饰因子。
With cancer often classified as a disease that has an important epigenetic component, natural compounds that have the ability to regulate the epigenome become ideal candidates for study. Humans have a complex diet, which illustrates the need to elucidate the mechanisms of interaction between these bioactive compounds in combination. The natural compounds withaferin A (WA), from the Indian winter cherry, and sulforaphane (SFN), from cruciferous vegetables, have numerous anti-cancer effects and some report their ability to regulate epigenetic processes. Our study is the first to investigate the combinatorial effects of low physiologically achievable concentrations of WA and SFN on breast cancer cell proliferation, histone deacetylase1 (HDAC1) and DNA methyltransferases (DNMTs). No adverse effects were observed on control cells at optimal concentrations. There was synergistic inhibition of cellular viability in MCF-7 cells and a greater induction of apoptosis with the combinatorial approach than with either compound administered alone in both MDA-MB-231 and MCF-7 cells. HDAC expression was down-regulated at multiple levels. Lastly, we determined the combined effects of these bioactive compounds on the pro-apoptotic BAX and anti-apoptotic BCL-2 and found decreases in BCL-2 and increases in BAX. Taken together, our findings demonstrate the ability of low concentrations of combinatorial WA and SFN to promote cancer cell death and regulate key epigenetic modifiers in human breast cancer cells.