Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology and Center for Cancer Prevention Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, NJ, 08854, USA.
Genes Nutr. 2012 Jan;7(1):11-8. doi: 10.1007/s12263-011-0233-y. Epub 2011 May 18.
Tocotrienols (T3s), members of the vitamin E family, exhibit potent anti-cancer, anti-oxidative, anti-inflammatory, and some other biological activities. To better understand the bioavailability and metabolism of T3s, T3s and their metabolites were identified in urine and fecal samples from mice on diet supplemented with mixed T3s using HPLC/electrochemical detection and liquid chromatography electrospray ionisation mass spectrometry (LC-ESI-MS). Whereas the short-chain metabolites carboxyethyl hydroxychromans (CEHCs) and carboxymethylbutyl hydroxychromans (CMBHCs) were the major metabolites of T3s, several new metabolites with double bonds were also identified. Similar to tocopherols, the majority of T3 metabolites were excreted as sulfate/glucuronide conjugates in mouse urine. The distribution of γ- and δ-T3 and γ-T3 metabolites were also determined in different organs as well as in urine and fecal samples from mice on diets supplemented with corresponding T3s. The synergistic anti-cancer actions of γ-T3 and atorvastatin (ATST) were studied in HT29 and HCT116 colon cancer cell lines. The combination greatly potentiated the ability of each individual agent to inhibit cancer cell growth and to induce cell cycle arrest and apoptosis. The triple combination of γ-T3, ATST, and celecoxib exhibited synergistic actions when compared with any double combination plus the third agent. Mechanistic studies revealed that the synergistic actions of γ-T3 and ATST could be attributed to their mediation of 3-hydroxy-3-methyl-glutaryl-CoA reductase, and the subsequent inhibition of protein geranylgeranylation. It remains to be determined whether such a synergy occurs in vivo.
生育三烯酚（T3s）是维生素 E 家族的成员，具有很强的抗癌、抗氧化、抗炎等生物活性。为了更好地了解 T3s 的生物利用度和代谢情况，我们使用高效液相色谱/电化学检测和液相色谱-电喷雾离子化质谱（LC-ESI-MS），在补充混合 T3s 的饮食的小鼠的尿液和粪便样本中鉴定了 T3s 和其代谢物。虽然短链代谢物羧乙基羟色烷（CEHCs）和羧甲基丁基羟色烷（CMBHCs）是 T3s 的主要代谢物，但也鉴定出了几种具有双键的新代谢物。与生育酚类似，T3 代谢物的大部分以硫酸盐/葡萄糖醛酸缀合物的形式从尿液中排出。还确定了不同器官以及补充相应 T3s 的饮食的小鼠尿液和粪便样本中 γ-和 δ-T3 和 γ-T3 代谢物的分布。在 HT29 和 HCT116 结肠癌细胞系中研究了 γ-T3 和阿托伐他汀（ATST）的协同抗癌作用。该组合大大增强了每个单独药物抑制癌细胞生长、诱导细胞周期停滞和细胞凋亡的能力。与任何双组合加第三种药物相比，γ-T3、ATST 和塞来昔布的三联组合表现出协同作用。机制研究表明，γ-T3 和 ATST 的协同作用可归因于它们对 3-羟-3-甲基戊二酰辅酶 A 还原酶的介导作用，以及随后对蛋白质 geranylgeranylation 的抑制作用。这种协同作用是否在体内发生仍有待确定。
