Investigation of the inhibitory mechanism of the hepatic metastasis in the colorectal carcinoma by synthesic retinoid, TAC-101

合成类维生素A TAC-101抑制结直肠癌肝转移的机制研究

基本信息

批准号：
14571249
负责人：
ITOH Hideaki
金额：
$ 1.73万
依托单位：
University of Occupational and Environmental Health
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

项目摘要

The presence of hepatic metastasis is one of the most important prognostic factors in colorectal cancer. This suggests that more effective suppressor of the progression and metastasis of colon cancer would significantly improve prognosis. Recently, RA (retinoic acid) has shown to be a potentially powerful anti-cancer agent, and acts in several types of cancer therapy. The mechanism of RA's affect on tumors appears to be related to its effects on proliferation and differentiation of tumor cells. 4-[3,5-bis (trimethylsilyl) benzamido] benzoic acid (TAC-101) is a novel retinobenzoic acid derivative and has a specific binding affinity to the retinoic acid receptors (RAR)-α and -β. TAC-101 has potent anti-proliferative, anti-angiogenic, and anti-tumor effects in vitro and in vivo. However, little is known about the detailed mechanism of TAC-101 function.Here, we investigate the mechanism of the anti-angiogenic effect and apoptosis induction of TAC-101. Hepatic metastases were induced by por … More tal injection of RCN-9 rat colonic cancer cells into F344 rats. TAC-101 was orally administered 5 days per week for four weeks, then liver tumors were immunohistochemically evaluated for microvascular density (MVD) and vascular endothelial growth factor (VEGF). Apoptotic index (A.I.) in the hepatic tumors was evaluated using immunohistochemistry for single-stranded DNA. The proliferative index (P.I.), Fas and Fas ligand were also immunohistochemically evaluated. Moreover, evaluation of apoptosis by TAC-101 in vitro using FACScan analysis was performed in the DLD-1 human colon cancer cell line.TAC-101 significantly reduced both MVD and VEGF expression. Northern blot analysis and ELISA indicated that TAC-101 efficiently inhibited production of VEGF mRNA and protein in DLD-1 cells in a time-and dose-dependent manner. TAC-101 significantly decreased P. I. but increased A. I. in the hepatic metastatic tumors. TAC-101 did not affect the expression of Fas ligand, but obviously increased the expression of Fas in the metastatic tumors. Moreover, TAC-101 induced early apoptosis in DLD-1 cells in a time dependent manner in vitro.These findings suggest that TAC-101 may inhibit progression and metastasis in colon cancer by interfering with tumor production of VEGF. Moreover, TAC-101 may induced apoptosis partially through enhanced Fas expression. Less

肝转移的存在是大肠癌中最重要的预后因素之一。这表明结肠癌进展和转移的更有效抑制剂将显着改善预后。最近，RA（视黄酸）已证明是一种潜在的强大抗癌剂，并作用于几种类型的癌症治疗。 RA对肿瘤的影响的机制似乎与其对肿瘤细胞增殖和分化的影响有关。 4- [3,5-双基（三甲基甲硅烷基）苯甲酰二甲酸（TAC-101）是一种新型的视网膜苯甲酸衍生物，具有特定的结合亲和力，与视黄酸受体（RAR）-α和-β具有特异性的结合亲和力。 TAC-101在体外和体内具有潜在的抗增殖，抗血管生成和抗肿瘤作用。但是，关于TAC-101功能的详细机制知之甚少。在这里，我们研究了TAC-101的抗血管生成作用和凋亡诱导的机制。肝转移是通过POR诱导的……将RCN-9大鼠结肠癌细胞进一步注射到F344大鼠中。 TAC-101每周口服5天4周，然后对肝肿瘤进行免疫组织化学评估微血管密度（MVD）和血管内皮生长因子（VEGF）。使用免疫组织化学评估单链DNA的肝肿瘤中的凋亡指数（A.I.）。还对增殖指数（P.I.），FAS和FAS配体进行了免疫组织化学评估。此外，使用FACSCAN分析在DLD-1人类结肠癌细胞系中对TAC-101对凋亡进行评估。TAC-101显着降低了MVD和VEGF的表达。 Northern印迹分析和ELISA表明，TAC-101在DLD-1细胞中有效抑制了VEGF mRNA和蛋白质的产生，并依赖于剂量依赖性。 TAC-101显着降低了P. I.，但在肝转移性肿瘤中增加了A. I.。 TAC-101不影响FAS配体的表达，但显然增加了FAS在转移性肿瘤中的表达。此外，TAC-101在体外诱导了DLD-1细胞的早期凋亡。这些发现表明，TAC-101可以通过与VEGF的肿瘤产生相互作用来抑制结肠癌的进展和转移。此外，TAC-101可能通过增强的FAS表达会部分诱导凋亡。较少的