Ferrer Paula, Asensi Miguel, Segarra Ramón, Ortega Angel, Benlloch María, Obrador Elena, Varea María T, Asensio Gregorio, Jordá Leonardo, Estrela José M
Department of Physiology, University of Valencia, Spain.
Neoplasia. 2005 Jan;7(1):37-47. doi: 10.1593/neo.04337.
Inhibition of cancer growth by resveratrol (trans-3,5,4'-trihydroxystilbene; RESV), a phytoalexin present in many plant species, is limited by its low bioavailability. Pterostilbene (3,5-dimethoxy-4'-hydroxystilbene; PTER) and quercetin (3,3',4',5,6-pentahydroxyflavone; QUER), two structurally related and naturally occurring small polyphenols, show longer half-life in vivo. In vitro growth of highly malignant B16 melanoma F10 cells (B16M-F10) is inhibited (56%) by short-time exposure (60 min/day) to PTER (40 microm) and QUER (20 microm) (approximate mean values of plasma concentrations measured within the first hour after intravenous administration of 20 mg/kg each polyphenol). Intravenous administration of PTER and QUER (20 mg/kg per day) to mice inhibits (73%) metastatic growth of B16M-F10 cell in the liver, a common site for metastasis development. The anti-metastatic mechanism involves: 1) a PTER-induced inhibition of vascular adhesion molecule 1 expression in the hepatic sinusoidal endothelium, which consequently decreases B16M-F10 cell adhesion to the endothelium through very late activation antigen 4; and 2) a QUER- and PTER-induced inhibition of Bcl-2 expression in metastatic cells, which sensitizes them to vascular endothelium-induced cytotoxicity. Our findings demonstrate that the association of PTER and QUER inhibits metastatic melanoma growth and extends host survival.
白藜芦醇（反式 -3,5,4'-三羟基芪；RESV）是许多植物物种中存在的一种植保素，其对癌症生长的抑制作用因生物利用度低而受限。紫檀芪（3,5 - 二甲氧基 -4'-羟基芪；PTER）和槲皮素（3,3',4',5,6 - 五羟基黄酮；QUER）是两种结构相关的天然小分子多酚，在体内显示出更长的半衰期。高恶性B16黑色素瘤F10细胞（B16M - F10）的体外生长在短时间暴露（每天60分钟）于PTER（40微摩尔）和QUER（20微摩尔）时受到抑制（56%）（每种多酚静脉注射20毫克/千克后第一小时内测得的血浆浓度近似平均值）。给小鼠静脉注射PTER和QUER（每天20毫克/千克）可抑制B16M - F10细胞在肝脏中的转移生长，肝脏是转移发生的常见部位。抗转移机制包括：1）PTER诱导肝窦内皮细胞中血管黏附分子1表达的抑制，从而通过极晚期活化抗原4减少B16M - F10细胞与内皮细胞的黏附；2）QUER和PTER诱导转移细胞中Bcl - 2表达的抑制，使它们对血管内皮细胞诱导的细胞毒性敏感。我们的研究结果表明，PTER和QUER联合使用可抑制转移性黑色素瘤生长并延长宿主存活时间。
