HUMAN BREAST CANCER CELL GROWTH INHIBITION BY VITAMIN E

维生素 E 抑制人类乳腺癌细胞生长

基本信息

批准号：
6773891
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
项目类别：
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

项目摘要

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）目标是研究 VES（维生素 E 琥珀酸酯；RRR-α-生育酚琥珀酸酯）的作用，是一种有效的人类乳腺癌细胞凋亡的诱导剂，但不是正常乳腺细胞凋亡的诱导剂上皮细胞。申请人的研究表明，VES 可以恢复两者转化生长因子-β (TGF-β) 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稳态信号通路具有抵抗力。在这个申请人提议调查的竞争性继续申请参与 VES 启动人类细胞凋亡的关键信号事件 MDA-MB-435 乳腺癌细胞。正常人乳腺上皮细胞（HMEC）和永生化、非致瘤性人乳腺上皮 MCF-10A 细胞对 VES 诱导的细胞凋亡不敏感，但对 TGF-β 和将研究 Fas 诱导的细胞命运以进行比较。目标1将表征 TGF-β 信号转导途径的组成部分有助于 VES 诱导的细胞凋亡。目标 2 将表征 Fas 信号参与 VES 诱导细胞凋亡的转导事件。目标 3 将进行调查 VES 处理细胞的凋亡决定阶段，重点是 Bax 和产生下游执行阶段的线粒体介导的事件调解员。 VES 与配体（TGF-β1 和抗 Fas 激动剂）之间的比较抗体）介导的 MDA-MB-435、HMEC 和 MCF-10A 细胞中的事件将解决 VES选择性诱导癌症细胞凋亡能力的分子基础细胞，但不在正常细胞或永生化但非致瘤细胞中。期望生成的数据将增加有关 TGF-beta 和 Fas 的基础知识正常细胞和癌细胞中的信号传导，并将提供更好的理解 VES（一种有效的促凋亡剂）如何诱导细胞死亡。的一部分这些机制研究的意义在于药物的潜在用途例如用于人类乳腺癌化疗的 VES。这种可能性已经被最近的证明表明 VES 以太类似物是一种有效的、人类临床前异种移植模型中的口服活性化疗剂乳腺癌。这些类型研究的意义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的细胞内信号转导分子可以有针对性地设计基于机制的药物以实现改善癌症细胞杀伤。