Studies on apoptosis-inducers targeted for the molecules associated with the induction of apoptosis in cancer cells

针对癌细胞凋亡诱导相关分子的凋亡诱导剂研究

• 批准号: 11672182
• 负责人: NAKAYA Kazuyasu
• 金额: $ 2.24万
• 依托单位: Showa university
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11672182/
• 关键词: Apoptosis; Apoptosis-inducers; Molecular target; Sophoranone; Flavonoid; 分子標的; フラボノイド; 標的

Screening of various natural products in a search for novel inducers of apoptosis in human leukemia cells led us to identify the strong apoptosis-inducing activity in a fraction extracted with methanol from the traditional Chinese medicine Shan Dou Gen, which is isolated from the roots of Sophora subprostrata Chun et T.Chen and is used as an antidote and an anodyne. We purified the compound that induced in human leukemia cells and identified it as sophoranone. Sophoranone inhibited cell growth and induced apoptosis in various lines of cells from human solid tumors, with 50% inhibition of growth of human stomach cancer MKN7 cells at 1.2±0.3 μM.The growth-inhibitory and apoptosis-inducing activities of sophoranone for leukemia U937 cells were very much stronger than those of other flavonoids, such as daidzein, genistein, and quercetin. At the early stages of treatment of U937 cells with sophoranone, reactive oxygen species (ROS) were formed, mitochondrial permeability pores were opened, and cytochrome c was released from mitochondria. Cytochrome c was also released upon treatment of isolated mitochondria with sophoranone. Inhibitors of complexes III and IV, but not complexes I and II, of the mitochondrial respiratory chain prevented the release of cytochrome c from isolated mitochondria by sophoranone, as well as the induction of apoptosis in U937 cells in response to sophoranone. Our results indicate that sophoranone might be a unique apoptosis-inducing anticancer agent that targets mitochondria.

筛选各种天然产物，寻找新的诱导人白血病细胞凋亡的诱导剂，使我们确定了强烈的诱导凋亡的活性，从传统中药山豆根，这是从根中分离的槐subprostrata春等T.陈，并被用作解毒剂和止痛剂用甲醇提取的馏分。我们纯化了诱导人白血病细胞的化合物，并鉴定其为槐酮。槐烷酮对多种人实体瘤细胞株均有生长抑制和诱导凋亡作用，在1.2±0.3 μM浓度下，对人胃癌MKN 7细胞的生长抑制率为50%，对白血病U937细胞的生长抑制和诱导凋亡作用明显强于其他黄酮类化合物，如大豆黄酮、染料木素和槲皮素。在槐酮处理U937细胞的早期阶段，活性氧（ROS）形成，线粒体渗透孔打开，线粒体释放细胞色素c。细胞色素c也释放后，与槐酮处理分离的线粒体。复合物III和IV的抑制剂，但不是复合物I和II，线粒体呼吸链阻止释放细胞色素c从分离的线粒体槐酮，以及诱导细胞凋亡的U937细胞响应槐酮。我们的研究结果表明，槐酮可能是一个独特的凋亡诱导的抗癌剂，靶向线粒体。

项目成果

Koji Kusano, Hiroyuki Naito, Toshihiro Aiuchi, Shigeo Nakajo, and Kazuyasu Nakaya.: "Role of calcium on ATP-and bradykinin-induced mucin secretion from human pulmonary mucoepidermoid carcinoma cell lines."Pharm.Pharmacol.Commun.. 6. 369-374 (2000)

Koji Kusano、Hiroyuki Naito、Toshihiro Aiuchi、Shigeo Nakajo 和 Kazuyasu Nakaya。：“钙对人肺粘液表皮样癌细胞系 ATP 和缓激肽诱导的粘蛋白分泌的作用。”Pharm.Pharmacol.Commun.. 6. 369-

Yutaka Masuda, Mie Nakaya, Toshihiro Aiuchi, Sachiko Hashimoto, Shigeo Nakajo, and Kazuyasu Nakaya.: "Geranylgeraniol induces apoptosis by a caspase-3-like protease dependent activation of a c-Jun N-terminal kinase signaling cascade mechanism different fr

Yutaka Masuda、Mie Nakaya、Toshihiro Aiuchi、Sachiko Hashimoto、Shigeo Nakajo 和 Kazuyasu Nakaya。：“香叶基香叶醇通过 c-Jun N 端激酶信号级联机制不同的 c-Jun N 末端激酶信号级联机制的 caspase-3 样蛋白酶依赖性激活来诱导细胞凋亡

Kazuki Iwama et al.: "Apoptosis induced by arsenic trioxide in leukemia U937 cells is dependent on activation of p38, inactivation of ERK and on superoxide."International Journal of Cancer. 92. (2001)

Kazuki Iwama 等人：“白血病 U937 细胞中三氧化二砷诱导的细胞凋亡依赖于 p38 的激活、ERK 的失活和超氧化物。”国际癌症杂志。

Koji Kusano et al.: "Role of calcium on ATP-and bradykinin-induced mucin secretion from human pulmonary mucoepidermoid carcinoma."Pharm.pharmacal.Commun.. 6. 369-374 (2000)

Koji Kusano 等人：“钙对 ATP 和缓激肽诱导的人肺粘液表皮样癌粘蛋白分泌的作用。”Pharm.pharmacal.Commun. 6. 369-374 (2000)

Yutaka Masuda et al.: "Geranylgeraniol induces apoptosis by a caspase-3-like protease dependent activation of a c-Jun N-terminal kinase signaling cascade"Leukemia Research. 24. 937-950 (2000)

Yutaka Masuda 等人：“香叶基香叶醇通过 c-Jun N 端激酶信号级联的 c-Jun N 末端激酶信号级联的 caspase-3 样蛋白酶依赖性激活来诱导细胞凋亡”白血病研究。