Human Breast Cancer Cell Growth Inhibition by Vitamin E

维生素 E 抑制人乳腺癌细胞生长

• 批准号: 6986357
• 负责人: KIMBERLY KLINE
• 金额: $ 28.69万
• 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 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6986357
• 关键词: CD95 molecule; JUN kinase; MCF7 cell; apoptosis; biological signal transduction; breast neoplasms; cell growth regulation; combination cancer therapy; combination chemotherapy; doxorubicin; drug design /synthesis /production; enzyme activity; gene induction /repression; growth factor receptors; laboratory mouse; lung neoplasms; metastasis; mitogen activated protein kinase; neoplasm /cancer pharmacology; neoplastic cell; neoplastic growth; receptor expression; tissue /cell culture; tocopherols; vitamin analog; xenotransplantation

DESCRIPTION (provided by applicant): Breast cancer incidence and mortality remains a major health problem worldwide. We have developed a novel vitamin E analog referred to as alpha-TEA that inhibits growth of human cancer cells and does not exhibit toxicities to normal cells and tissues. We hypothesize that alpha-TEA will be effective as a chemotherapeutic agent for breast cancer. Goals are to investigate the ability of alpha-TEA to: (i) enhance survival of NU/NU mice transplanted with human MDA-MB-435 breast cancer cells, (ii) reduce lung metastases following treatment after removal of primary tumors, and (iii) act cooperatively in combination with doxorubicin in reducing tumor burden and metastasis. Additionally, we will study alpha-TEA's mechanisms of action as an antitumor agent. Proposed studies are supported by data showing alpha-TEA to: (i) significantly reduce tumor burden and metastases in a human MDA-MB-435 breast cancer xenograft model, (ii) sensitize MDA-MB-435 cells to low dose doxorubicin- induced apoptosis in cell culture, and (iii) induce tumor cell death by blocking cell survival signaling and by restoring pro-apoptotic signaling pathways. 3 key events in alpha-TEA-mediated apoptosis in human breast cancer cells are: blockage of prosurvival HER2/ AKT/FLIP signaling; restoration of TRAIL7DR5 and Fas/Fas Ligand apoptotic signaling pathways; and signaling of apoptosis via both mitochondria-dependent and -independent pathways. Proposed studies are highly significant in that they are focused on pre-clinical development of a promising, new therapeutic agent for treatment of breast cancer. Proposed mechanistic studies have a high potential for identifying and characterizing dysregulated signaling pathways/events that are modifiable and therefore may serve as important molecular targets for treatment of breast cancer.

描述（由申请人提供）：乳腺癌的发病率和死亡率仍然是世界范围内的一个主要健康问题。我们开发了一种新型维生素 E 类似物，称为 α-TEA，它可以抑制人类癌细胞的生长，并且不会对正常细胞和组织产生毒性。我们假设 α-TEA 作为乳腺癌化疗药物是有效的。目标是研究 α-TEA 的能力：(i) 提高移植人 MDA-MB-435 乳腺癌细胞的 NU/NU 小鼠的存活率，(ii) 在切除原发肿瘤后减少治疗后的肺转移，以及（ iii)与多柔比星联合协同作用，减少肿瘤负荷和转移。此外，我们将研究 α-TEA 作为抗肿瘤剂的作用机制。拟议的研究得到了数据的支持，数据显示 α-TEA 可以：（i）显着减少人 MDA-MB-435 乳腺癌异种移植模型中的肿瘤负荷和转移，（ii）使 MDA-MB-435 细胞对低剂量阿霉素诱导敏感细胞培养物中的细胞凋亡，以及（iii）通过阻断细胞存活信号传导和恢复促凋亡信号传导途径诱导肿瘤细胞死亡。 α-TEA 介导的人乳腺癌细胞凋亡的 3 个关键事件是： 阻断促生存 HER2/AKT/FLIP 信号传导； TRAIL7DR5 和 Fas/Fas Ligand 凋亡信号通路的恢复；以及通过线粒体依赖性和非依赖性途径进行细胞凋亡的信号传导。 拟议的研究非常重要，因为它们专注于一种有前途的乳腺癌治疗新治疗剂的临床前开发。所提出的机制研究在识别和表征可修改的失调信号通路/事件方面具有很高的潜力，因此可以作为乳腺癌治疗的重要分子靶点。