Anti-tumor actions of various stiIbene derivatives through Toll-like receptors

据报道，白藜芦醇(3，4‘，5-三羟基二苯乙烯)的抗肿瘤和抗转移作用可能与抑制肿瘤诱导的血管生成有关。为了寻找比白藜芦醇更强的抗癌药物，本研究通过抑制血管生成因子(如血管内皮生长因子的产生、血管内皮生长因子受体-2的表达或磷酸化、基质金属蛋白酶的表达、环氧合酶-2的表达、缺氧诱导因子-L的α表达和肿瘤相关巨噬细胞的激活)来观察21种合成和/或天然二苯乙烯类化合物的作用。主要研究结果如下：(1)不同饮食对荷瘤小鼠血管内皮细胞生长因子、低密度脂蛋白诱导因子-1α和单核细胞ChE-1〓-1表达的影响：移植瘤后血浆瘦素、单核细胞趋化蛋白-1等血管生成因子表达增加，而抗血管生成因子脂联素…表达降低。更多的肿瘤。此外，还发现高脂、高蔗糖和高胆固醇饮食的小鼠肿瘤组织中血管内皮生长因子、缺氧诱导因子-Lα和单核细胞趋化蛋白-1的表达水平高于低脂/低蔗糖饮食的小鼠。这些结果提示，肿瘤生长和转移的加速可能是通过巨噬细胞的聚集和激活而增加血管生成因子。(2)天然产物通过激活小肠免疫功能发挥抗肿瘤和抗转移作用。低分子水溶性β-葡聚糖腹腔和口服给药抑制小鼠结肠癌26细胞移植瘤的生长和肝转移。结肠癌26荷瘤小鼠小肠自然杀伤细胞和干扰素γ阳性细胞数均低于正常小鼠。(3)合成的和天然的二苯乙烯类化合物，2，3-，3，4-和4，4‘-二羟基二苯乙烯类化合物通过抗血管生成作用，抑制结肠26细胞基质金属蛋白酶-9的产生，血管内皮生长因子诱导的人脐静脉内皮细胞迁移和血管内皮生长因子诱导的人脐静脉内皮细胞1或5μ血管生成，从而发挥抗肿瘤活性。5-三羟基二苯乙烯(5-三羟基二苯乙烯)在25或50μM时抑制MMP9的产生和血管内皮细胞的迁移，因此，三种二羟基二苯乙烯对结肠26细胞MMP9产生和血管内皮细胞迁移的抑制作用强于白藜芦醇。3种二羟基二苯乙烯类化合物(8 mg/kg，ip)均能抑制结肠癌26室荷瘤小鼠的肿瘤新生血管和结肠癌26室小鼠的肿瘤生长。此外，二羟基二苯乙烯类化合物对荷瘤TLR-4突变小鼠肿瘤生长和转移的影响的研究正在进行中。较少

It has been reported that the antitumor and antimetastatic actions of resveratrol (3,4',5-trihydroxystilbene) might be due to the inhibition of tumor-induced angiogenesis. To search for anticancer agents with stronger activity than resveratrol, this study was examined the effects of 21 syntehtic and/or natural stilbenes through the inhibition of angiogenic factors (e.g. VEGF production, VEGFR-2 expression or phosphorylation, MMP expression, COX-2 expression, HIF-lα expression and tumor-associated macrophage activation). The summary of research results were described as follows;(1) Effects of various diet an tumor growth and metastasis through the activation of vascular endothelia growth factor (VEGF), hypo〓 inducible factor (HIF) -1α and monocyte che〓-1 (MCP I) expressions in tumor-bearing miceAngiogenic factors such as plasma leptin and MCP-1 were increased after the implantation of tumors, wheras conversely, an anti-angiogenic factor, adiponectiin, was reduced after the implantation … More of tumors. Furthermore, it was found that VEGF, HIF-lα and MCP-1 expression levels in tumors of mice fad the high-fat, the high-sucrose, or the high-cholesterol diets were increased compared to those of mice fed the low-fat/low-sucrose diet. These findings suggest that the acceleration of tumor growth and metastasis may be due to the increase of angiogenic factors through the macrophage accumulation and activation of tumors.(2) Antitumor and antimetastatic actions of natural products through the activation of immune function of small intestine The intraperitoneal and oral administration of low-molecular weight water-soluble β-glucan inhibited the tumor growth and liver metastasis in mice intraslenically implanted with colon 26 cells. The number of natural killer (NK)- and interferon (IFN)-γ-positive cells in the small intestine of colon 26-bearing mice were lower than those in nor mal mice. The intraperitoneally and orally administered low-molecular-weight water-soluble 3-glucan prevented the reduction of the number of NK- and IFN-γ-positive cells induced by the tumor.(3) Anti-tumor activities of synthetic and natural stlbenes through anti-angiogenic action Among synthetic and natural 21 stilbenes, 2,3-, 3,4- and 4,4'-dihydroxystilbenes inhibited the matrix metalloproteinase (MMP)-9 production in colon 26 cells, vascular endothelial growth factor (VEGF)-induced human umbilical vein endothelial cell (HUVEC) migration and VEGF-induced angiogenesis at 1 or 5 μM. Resveratrol (3,4',5-trihydroxystilbene) inhibited the MMP-9 production in colon 26 cells and VEGF-induced HUVEC migration at 25 or 50 μM. Thus, the inhibition of MMP-9 production in colon 26 cells and VEGF-induced HUVEC migration by three dihydroxystilbenes were greater than those of resveratrol. The three dihydroxystilbenes (8 mg/kg, ip) inhibited the tumor-induced neovascularization in colon 26-packed chamber-bearing mice and the tumor growth in colon 26-baering mice. Further, studies are in progress to examine the effects of dihydroxystilbenes on tumor growth and metastasis in tumor-bearing TLR-4 mutant mice. Less