Development of a nobel strategy for chemoprevention of colorectal carcinogenesis by using newly synthesized organic compounds derived from natural dietary constituents

使用源自天然膳食成分的新合成有机化合物开发化学预防结直肠癌的诺贝尔策略

• 批准号: 16590571
• 负责人: SHIBATA Hiroyuki
• 金额: $ 2.05万
• 依托单位: TOHOKU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590571/
• 关键词: beta-catenin; Ki-Ras; Cyclin-D1; c-Myc; erbb2; chemoprevention; phytochemical; β-catenin; Ki-ras; cyclin D1; erbb2; 家族性大腸腺腫症; 化学発癌予防

Curcumin is a dietary constituent of turmeric that is widely used as a spice. Curcumin is a well-studied phytochemical that has a potential to suppress the growth of many cancer cell lines, while that has less toxicity as it is used for daily food. In this study, we have raised the goal to synthesize the new compounds from curcumin bearing the strengthen ability to suppress the growth of tumor cells, but keeping its less toxicity, and to establish a nobel strategy for medication of cancer treatment. The first cycle of the screening, we synthesized a new curcumin analog, GO-035 that have 4 times higher growth suppressive ability. Then we have synthesized over 50 compounds derived from GO-035. Finally two analogs termed GO-Y030 and GO-Y031 have been found out that have 40 times or more growth suppressive abilities against colorectal cancer cell lines. The common characteristic feature of these compounds is a pentanoid having the symmetrical addition of the alkoxy groups to the aromatic rings at both ends. These compounds have a stronger growth suppressive potential against a variety of cancer cell lines derived from stomach, colon, lung, pancreas, ovary, melanoma and so on, compared with chemotherapeutic agents such as cis-platine, 5-FU and irinotecan. The improvements of mechanical aspects of these compounds are the higher potentials to induce a G2/M phase arrest, apoptosis and down-regulation of various oncoproteins including beta-catenin, Ki-Ras, Cyclin-D1, c-Myc and erbb2 at much lower concentration than curcumin. On the other hands, there is no harmful effect on the primary hepatocytes at even 100 micromolar. There is no toxic effect on the mice fed with these conpounds (0.1% (w/w)in daily diet). These features of the compounds is thought to be ideal for not only chemotherapy but also chemoprevention.

姜黄素是姜黄的一种膳食成分，姜黄被广泛用作香料。姜黄素是一种经过充分研究的植物化学物质，它有可能抑制许多癌细胞系的生长，而姜黄素的毒性较小，因为它被用作日常食物。本研究提出了以姜黄素为原料合成抑制肿瘤细胞生长能力增强，但毒性较低的新化合物，建立抗癌药物治疗的诺贝尔策略的目标。在第一轮筛选中，我们合成了一种新的姜黄素类似物GO-035，其生长抑制能力提高了4倍。然后我们合成了50多个从GO-035衍生的化合物。最后发现两种类似物GO-Y030和GO-Y031对结直肠癌细胞株的生长抑制能力达到40倍以上。这些化合物的共同特征是在两端芳香环上对称加成烷氧基的五烷类化合物。与顺铂、5-FU和伊立替康等化疗药物相比，这些化合物对来自胃、结肠、肺、胰腺、卵巢、黑色素瘤等多种癌细胞系具有更强的生长抑制潜力。这些化合物在机械方面的改进是在比姜黄素低得多的浓度下诱导G2/M期阻滞、凋亡和下调各种癌蛋白，包括β -catenin、Ki-Ras、Cyclin-D1、c-Myc和erbb2的电位更高。另一方面，即使在100微摩尔浓度下，对原代肝细胞也没有有害影响。这些化合物（日粮中0.1% (w/w)）对小鼠无毒性作用。这些化合物的这些特性被认为不仅是化疗的理想选择，也是化学预防的理想选择。

项目成果

特許権

专利权

• 发表时间: 2018

化合物、抗癌剤、発癌予防財、β-Catenin分解剤

化合物、抗癌剂、癌症预防剂、β-catenin分解剂

• 发表时间: 2005

A nobel germline mutation of the LKB1gene in a patient with Peutz-Jeghers syndrome with early-onset gastric cancer.

患有早发性胃癌的 Peutz-Jeghers 综合征患者中 LKB1 基因的诺贝尔种系突变。

• 发表时间: 2004
• 期刊: J.Gastroenterol. 39
• 作者: Kikuta K;Masamune A;et al.;Takahashi M et al.
• 通讯作者: Takahashi M et al.