A Redox-Inactive Derivative of Tocotrienol Suppresses Tumor Growth of Mesothelioma Cells in a Xenograft Model
A Redox-Inactive Derivative of Tocotrienol Suppresses Tumor Growth of Mesothelioma Cells in a Xenograft Model
复制标题
DOI：
10.1248/bpb.b18-00924
复制
发表时间：
2019-06-01
影响因子：
2
通讯作者：
Yano, Tomohiro
中科院分区：
文献类型：
--
作者：
Sato, Ayami;Arai, Tsunetaka;Yano, Tomohiro
恶性间皮瘤（MM）是一种侵袭性癌症，预后差。我们专注于生育三烯酚（T3）的抗癌活性，并报告了一种新的氧化还原活性的T3衍生物（6-O-羧基丙基-α-生育三烯酚; T3 E）在体外对MM细胞生长的抑制作用比T3更强。此外，我们还揭示了T3 E参与抗MM作用的一些机制。然而，T3 E在体内的作用仍不清楚。在这项研究中，我们使用小鼠比较了T3 E和T3的血浆浓度，以阐明药代动力学的差异。口服T3或T3 E后依次采集血液，并通过HPLC分析血浆浓度。T3和T3 E血浆浓度-时间曲线下面积（AUC（0- 24 h））为T3的2倍。此外，我们使用移植了人MM细胞（H2052细胞系）的小鼠异种移植模型评价了T3 E口服给药对肿瘤生长的影响。小鼠经口给予150 mg/kg T3 E，每2天1次，持续10天，肿瘤体积显著缩小，体重无减轻，表明T3 E具有潜在的抗MM作用。
Malignant mesothelioma (MM) is an aggressive cancer with poor prognosis. We focused on the anticancer activity of tocotrienol (T3) and have reported that a new redox-inactive T3 derivative (6-O-carboxypropyl-alpha-tocotrienol; T3E) exerts stronger inhibitory effects on MM cell growth than that of T3 in vitro. Furthermore, we have revealed some mechanisms of T3E that are involved in anti-MM effects. However, the effect of T3E in vivo remains unclear. In this study, we compared the plasma concentrations of T3E to that of T3 using mice to clarify differences in pharmacokinetics. Blood was sequentially collected after oral administration of T3 or T3E, and plasma concentrations were analyzed by HPLC. The area under the plasma T3 and T3E concentration-time curve from 0 to 24h (AUC(0-24h)) of T3E was two times higher than that of T3. In addition, we evaluated the effect of T3E oral administration on tumor growth using a xenograft model of mice that were transplanted with human MM cells (H2052 cell line). Tumor volume was significantly reduced without body weight loss in mice orally administered 150 mg/kg T3E once per 2d for 10d, which suggests that T3E has potential anti-MM effects.