Emmert Sans W, Desai Dhimant, Amin Shantu, Richie John P
Department of Public Health Sciences, Penn State Hershey Cancer Institute, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
Bioorg Med Chem Lett. 2010 Apr 15;20(8):2675-9. doi: 10.1016/j.bmcl.2010.01.044. Epub 2010 Jan 20.
Epidemiological and laboratory studies have highlighted the potent chemopreventive effectiveness of both dietary selenium and cruciferous vegetables, particularly broccoli. Sulforaphane (SFN), an isothiocyanate, was identified as the major metabolite of broccoli responsible for its anti-cancer properties. An important mechanism for SFN chemoprevention is through the enhancement of glutathione (GSH), the most abundant antioxidant in animals and an important target in chemoprevention. Enhancement of GSH biosynthetic enzymes including the rate-limiting glutamate cysteine ligase (GCL), as well as other Phase II detoxification enzymes results from SFN-mediated induction of the nuclear factor-erythroid 2-related factor 2 (Nrf2)/antioxidant response elements (ARE) signaling pathway. While isothiocyanate compounds such as SFN are among the most potent Nrf2 inducers known, we hypothesized that substitution of sulfur with selenium in the isothiocyanate functional group of SFN would result in an isoselenocyanate compound (SFN-isoSe) with enhanced Nrf2 induction capability. Here we report that SFN-isoSe activated an ARE-luciferase reporter in HepG2 cells more potently than SFN. It was also found that SFN-isoSe induced GCL and GSH in MEF cells in an Nrf2-dependent manner. Finally, we provide evidence that SFN-isoSe was more effective in killing HepG2 cancer cells, yet was less toxic to non-cancer MEF cells, than SFN. These data support our hypothesis, and suggest that SFN-isoSe and potentially other isoselenocyanates may be highly effective chemoprotective agents in vivo due to their ability to induce Nrf2 with low toxicity in normal cells and high efficiency at killing cancer cells.
流行病学和实验室研究都突出了膳食硒和十字花科蔬菜，尤其是西兰花的强大化学预防功效。异硫氰酸酯萝卜硫素（SFN）被确定为西兰花具有抗癌特性的主要代谢产物。SFN化学预防的一个重要机制是通过增强谷胱甘肽（GSH），它是动物体内最丰富的抗氧化剂，也是化学预防中的一个重要靶点。SFN介导的核因子红细胞2相关因子2（Nrf2）/抗氧化反应元件（ARE）信号通路的诱导，导致包括限速谷氨酸半胱氨酸连接酶（GCL）在内的GSH生物合成酶以及其他II相解毒酶的增强。虽然像SFN这样的异硫氰酸酯化合物是已知最强的Nrf2诱导剂之一，但我们推测在SFN的异硫氰酸酯官能团中用硒取代硫会产生一种具有增强的Nrf2诱导能力的异硒氰酸酯化合物（SFN-isoSe）。在此我们报告，SFN-isoSe在HepG2细胞中比SFN更有效地激活了ARE荧光素酶报告基因。还发现SFN-isoSe以Nrf2依赖的方式在MEF细胞中诱导GCL和GSH。最后，我们提供证据表明，与SFN相比，SFN-isoSe在杀死HepG2癌细胞方面更有效，但对非癌细胞MEF细胞的毒性更小。这些数据支持了我们的假设，并表明SFN-isoSe以及潜在的其他异硒氰酸酯可能是体内高效的化学保护剂，因为它们能够在正常细胞中以低毒性诱导Nrf2，并在杀死癌细胞方面具有高效率。
