期刊
MOLECULAR CANCER THERAPEUTICS
卷 12, 期 11, 页码 2400-2414出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-13-0142
关键词
-
类别
资金
- Cancer Research UK [C34999/A11344]
- Royal College of Surgeons of Edinburgh
- Breast Cancer Campaign [2011NovPR39]
- Oncotyrol [1.5]
- COMET-Competence Centers for Excellent Technologies by the Federal Ministry for Transport, Innovation, and Technology (BMVIT)
- Federal Ministry of Economy, Family, and Youth (BMWFJ)
- federal state Tyrol
- federal state Styria
- FWF, Austrian Science Foundation [MCBO ZFW011010-08]
- Austrian Cancer Society/Tyrol
Protein-protein interactions mediated through the C-terminal Bcl-2-associated athanogene (BAG) domain of BAG-1 are critical for cell survival and proliferation. Thioflavin S (NSC71948)-a mixture of compounds resulting from the methylation and sulfonation of primulin base-has been shown to dose-dependently inhibit the interaction between BAG-1 and Hsc70 in vitro. In human breast cancer cell lines, with high BAG-1 expression levels, Thioflavin S reduces the binding of BAG-1 to Hsc70, Hsp70, or CRAF and decreases proliferation and viability. Here, we report the development of a protocol for the purification and isolation of biologically active constituents of Thioflavin S and the characterization of the novel compound Thio-2. Thio-2 blocked the growth of several transformed cell lines, but had much weaker effects on untransformed cells. Thio-2 also inhibited the proliferation of melanoma cell lines that had become resistant to treatment with PLX4032, an inhibitor of mutant BRAF. In transformed cells, Thio-2 interfered with intracellular signaling at the level of RAF, but had no effect on the activation of AKT. Thio-2 decreased binding of BAG-1 to Hsc70 and to a lesser extent BRAF in vitro and in vivo, suggesting a possible mechanism of action. Given that tumors frequently develop resistance to kinase inhibitors during treatment, Thio-2 and related compounds may offer promising alternative strategies to currently available therapies. (C) 2013 AACR.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据