HUMAN BREAST CANCER CELL GROWTH INHIBITION BY VITAMIN E

维生素 E 抑制人类乳腺癌细胞生长

• 批准号: 6619607
• 负责人: KIMBERLY KLINE
• 金额: $ 27万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-08-01 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6619607
• 关键词: CD95 molecule; JUN kinase; MCF7 cell; apoptosis; biological signal transduction; breast neoplasms; cell growth regulation; cell proliferation; cytochrome c; enzyme activity; gene induction /repression; growth factor receptors; mammary epithelium; mitochondria; mitogen activated protein kinase; neoplastic cell; neoplastic growth; protooncogene; receptor expression; tocopherols; transfection; transforming growth factors; vitamin analog

DESCRIPTION: (Applicant's Abstract) Goals are to investigate the mechanisms of action of VES (vitamin E succinate; RRR-alpha-tocopheryl succinate), a potent inducer of apoptosis in human breast cancer cells but not normal mammary epithelial cells. The applicant's studies show that VES can restore both transforming growth factor-beta (TGF-beta) and Fas/CD95 impaired anti-proliferative and death signaling in human breast cancer cells that are resistant to these two important cell homeostatic signaling pathways. In this competing continuation application the applicant proposes to investigate critical signaling events involved in VES initiated apoptosis in human MDA-MB-435 breast cancer cells. Normal human mammary epithelial cells (HMECs) and immortalized, non-tumorigenic human mammary epithelial MCF-10A cells which are insensitive to VES induced apoptosis but responsive to both TGF-beta and Fas induced cell fates will be studied for comparative purposes. Aim 1 will characterize components of the TGF-beta signal transduction pathway contributing to VES-induced apoptosis. Aim 2 will characterize Fas signal transduction events involved in VES induced apoptosis. Aim 3 will investigate the decision phase of apoptosis in VES treated cells with emphasis on Bax and mitochondrial mediated events that produce downstream execution phase mediators. Comparisons between VES and ligand (TGF-beta1 and anti-Fas agonistic antibody) mediated events in MDA-MB-435, HMECs and MCF-10A cells will address the molecular basis of VES's selective ability to induce apoptosis in cancer cells but not in normal or immortalized but non-tumorigenic cells. Expectations are that data generated will increase basic knowledge about TGF-beta and Fas signaling in normal and cancer cells and will provide a better understanding of how VES, a potent pro-apoptotic agent, induces cell death. Part of the significance of these mechanistic studies lies in the potential use of agents like VES for chemotherapy of human breast cancer. This possibility has been strengthened by the recent demonstration that a VES ether analog is a potent, orally active chemotherapeutic agent in a preclinical xenograft model of human breast cancer. Another aspect of the significance of these type studies lies in the belief that better understanding of signaling events will lead to the identification of critical intracellular signal transduction molecules which can be targeted for design of mechanism-based drugs to achieve improved cancer cell killing.

描述：（申请人的摘要）目标是调查 VES的作用（维生素E琥珀酸酯； RRR-Alpha-托霍基琥珀酸），有效 人类乳腺癌细胞凋亡的诱导剂，但不是正常乳腺 上皮细胞。申请人的研究表明，VES可以恢复 转化生长因子-Beta（TGF-BETA）和FAS/CD95受损 人类乳腺癌细胞中的抗增殖和死亡信号传导 对这两个重要的细胞体内稳态信号通路有抵抗力。在这个 竞争延续申请申请人提议调查 VES涉及的关键信号事件引发了人类的凋亡 MDA-MB-435乳腺癌细胞。正常的人类乳腺上皮细胞（HMEC） 以及永生的非肿瘤人类乳腺上皮MCF-10A细胞，该细胞 对VES诱导的凋亡不敏感，但对TGF-beta和 FAS诱导的细胞命运将用于比较目的。目标1意志 表征TGF-beta信号转导途径的组件 导致VES诱导的凋亡。 AIM 2将表征FAS信号 VES引起的凋亡涉及的转导事件。 AIM 3将调查 VES处理的细胞中细胞凋亡的决策阶段，重点是Bax和 线粒体介导的事件，产生下游执行阶段 调解人。 VES和配体之间的比较（TGF-BETA1和抗FAS激动 抗体）在MDA-MB-435，HMEC和MCF-10A细胞中介导的事件将解决 VES选择性能力诱导癌症凋亡的分子基础 细胞，但不处于正常或永生，而是非肿瘤细胞。期望 生成的数据是否会增加有关TGF-BETA和FAS的基本知识 正常和癌细胞中的信号传导，将更好地理解 VES是一种有效的促凋亡剂，如何诱导细胞死亡。一部分 这些机械研究的意义在于潜在的用途 就像对人类乳腺癌化学疗法的VE一样。这种可能性已经 最近的演示加强了VES Ether类似物是有效的， 人类临床前异种移植模型中的口服化学治疗剂 乳腺癌。这些类型研究的重要性的另一个方面在于 相信更好地理解信号事件将导致 鉴定关键细胞内信号转导分子，这些分子 可以针对设计基于机制的药物以实现改善癌症的目标 杀死细胞。