Inhibition of cancer growth by resveratrol is related to its low bioavailability
Inhibition of cancer growth by resveratrol is related to its low bioavailability
复制标题
DOI：
10.1016/s0891-5849(02)00911-5
复制
发表时间：
2002-08-01
影响因子：
7.4
通讯作者：
Estrela, JM
中科院分区：
文献类型：
--
作者：
Asensi, M;Medina, I;Estrela, JM
研究了白藜芦醇（resveratrol， RES）生物利用度与其对肿瘤生长影响的关系。分别对家兔、大鼠和小鼠静脉注射和口服反式白藜芦醇（t-RES）后的组织RES水平进行了研究。静脉注射20mg t-RES/kg b.wt后血浆中RES的半衰期。实验时间非常短（如家兔为14.4分钟）。在所有研究的动物中，静脉或口服给药后血浆RES的最高浓度（例如，小鼠在口服20mg t-RES/kg后2.5分钟内达到2.6 +/- 1.0 muM）在前5分钟内达到。血管外（脑、肺、肝、肾）RES水平与血浆水平相似，均< 1 nmol/g新鲜组织。血浆或组织中RES均为转化态（至少99%）。肝细胞以剂量依赖的方式代谢t-RES（例如，在20mum tRES存在下，43 nmol t-RES/g X min），这意味着肝脏可以非常迅速地清除循环中的RES。体外实验中，t-RES以浓度依赖性的方式抑制b16黑色素瘤（B16M）细胞的增殖和活性氧（ROS）的产生（在5 AM t-RES存在下发现100%的肿瘤生长抑制）。在5 AM - t-RES存在下培养的B16M细胞中加入10 muM H2O2，重新激活细胞生长。口服t-RES （20 mg/kg，每天2次；或以23 mg/l加入饮用水中）不抑制接种于小鼠足垫的B16M的生长（固体生长）。然而，口服t-RES（如上所述）可降低脾内接种的B16M细胞的肝转移侵袭。其抗转移机制涉及t-RES （I muM）诱导的血管粘附分子I （VCAM-1）在肝窦内皮（HSE）中的表达抑制，从而通过极晚活化抗原4 （vla4）降低体外B16M细胞对内皮的粘附。(C) 2002爱思唯尔科学有限公司
The relationship between resveratrol (RES) bioavalability and its effect on tumor growth was investigated. Tissue levels of RES were studied after i.v. and oral administration of trans-resveratrol (t-RES) to rabbits, rats, and mice. Half-life of RES in plasma, after i.v. administration of 20 mg t-RES/kg b.wt., was very short (e.g., 14.4 min in rabbits). The highest concentration of RES in plasma, either after i.v. or oral administration (e.g., 2.6 +/- 1.0 muM in mice 2.5 min after receiving 20 mg t-RES/kg orally), was reached within the first 5 min in all animals studied. Extravascular levels (brain, lung, liver, and kidney) of RES, which paralleled those in plasma, were always < I nmol/g fresh tissue. RES measured in plasma or tissues was in the trans form (at least 99%). Hepatocytes metabolized t-RES in a dose-dependent fashion (e.g., 43 nmol of t-RES/g X min in the presence of 20 muM tRES), which means that the liver can remove circulating RES very rapidly. In vitro B 16 melanoma (B16M) cell proliferation and generation of reactive oxygen species (ROS) was inhibited by t-RES in a concentration-dependent fashion (100% inhibition of tumor growth was found in the presence of 5 AM t-RES). Addition of 10 muM H2O2 to B16M cells, cultured in the presence of 5 AM t-RES, reactivated cell growth. Oral administration of t-RES (20 mg/kg twice per day; or included in the drinking water at 23 mg/l) did not inhibit growth of B16M inoculated into the footpad of mice (solid growth). However, oral administration of t-RES (as above) decreased hepatic metastatic invasion of B16M cells inoculated intrasplenically. The antimetastatic mechanism involves a t-RES (I muM)-induced inhibition of vascular adhesion molecule I (VCAM-1) expression in the hepatic sinusoidal endothelium (HSE), which consequently decreased in vitro B16M cell adhesion to the endothelium via very late activation antigen 4 (VLA-4). (C) 2002 Elsevier Science Inc.