Human Breast Cancer Cell Growth Inhibition by Vitamin E

维生素 E 抑制人乳腺癌细胞生长

基本信息

批准号：
7446199
负责人：
KIMBERLY KLINE
金额：
$ 27.2万
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 2009-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7446199
关键词：
Adverse effects Aftercare Animal Model Apoptosis Apoptotic Breast Cancer Cell Breast Cancer Treatment CDKN1A gene Cancer Burden Cancer Cell Growth Cell Cycle Arrest Cell Death Cell Survival Cells Cultured Cells Cyclin D1 Data Development Dose Down-Regulation Doxorubicin ERBB2 gene Ethers Ethyl Ether Event Excision Exhibits Funding Goals Grant Growth Health Human Incidence Inhibition of Cell Proliferation Lung Mediating Mitochondria Molecular Target NU/NU Mouse Neoplasm Metastasis Normal Cell Pathway interactions Pharmaceutical Preparations Prevention Primary Neoplasm Property Proteins Publishing Research Personnel Signal Pathway Signal Transduction Tea Therapeutic Agents Tissues Tocopherols Toxic effect Transplantation Tumor Burden Tumor Necrosis Factor Ligand Superfamily Member 6 Up-Regulation Vitamin E Xenograft Model alpha Tocopherol analog antitumor agent base cancer cell chemotherapeutic agent insight malignant breast neoplasm mortality neoplastic cell novel novel therapeutics oncoprotein p21 pre-clinical prevent programs restoration survivin tumor tumor growth vitamin E succinate

项目摘要

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。

项目成果

期刊论文数量（37）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

RRR-alpha-tocopheryl succinate induction of prolonged activation of c-jun amino-terminal kinase and c-jun during induction of apoptosis in human MDA-MB-435 breast cancer cells.

RRR-α-生育酚琥珀酸酯在诱导人 MDA-MB-435 乳腺癌细胞凋亡过程中诱导 c-jun 氨基末端激酶和 c-jun 的延长激活。

DOI：
发表时间：
1998
期刊：
Molecular carcinogenesis
影响因子：
4.6
作者：
Yu,W;Simmons-Menchaca,M;You,H;Brown,P;Birrer,MJ;Sanders,BG;Kline,K
通讯作者：
Kline,K

RRR-gamma-tocopherol induces human breast cancer cells to undergo apoptosis via death receptor 5 (DR5)-mediated apoptotic signaling.

DOI：
10.1016/j.canlet.2007.10.008
发表时间：
2008-02
期刊：
Cancer letters
影响因子：
9.7
作者：
Weiping Yu;Sook-Kyung Park;Linjiao Jia;Richa Tiwary;W. W. Scott-W.;Jing Li;Pei Wang;Marla Simmons‐Menchaca;B. G. Sanders;K. Kline
通讯作者：
Weiping Yu;Sook-Kyung Park;Linjiao Jia;Richa Tiwary;W. W. Scott-W.;Jing Li;Pei Wang;Marla Simmons‐Menchaca;B. G. Sanders;K. Kline

RRR-alpha-tocopheryl succinate-induced apoptosis of human breast cancer cells involves Bax translocation to mitochondria.

DOI：
发表时间：
2003-05
期刊：
Cancer research
影响因子：
11.2
作者：
Weiping Yu;B. G. Sanders;K. Kline
通讯作者：
Weiping Yu;B. G. Sanders;K. Kline

Downregulation of Epidermal Growth Factor Receptor Expression Contributes to alpha-TEA's Proapoptotic Effects in Human Ovarian Cancer Cell Lines.

DOI：
10.1155/2010/824571
发表时间：
2010
期刊：
Journal of oncology
影响因子：
0
作者：
Shun MC;Yu W;Park SK;Sanders BG;Kline K
通讯作者：
Kline K

In vitro and in vivo evaluation of anticancer actions of natural and synthetic vitamin E forms.

天然和合成维生素 E 形式的抗癌作用的体外和体内评估。

DOI：
10.1002/mnfr.200700254
发表时间：
2008
期刊：
Molecular nutrition & food research
影响因子：
5.2
作者：
Yu,Weiping;Jia,Li;Wang,Pei;Lawson,KarlaA;Simmons-Menchaca,Marla;Park,Sook-Kyung;Sun,Luzhe;Sanders,BobG;Kline,Kimberly
通讯作者：
Kline,Kimberly