期刊
CANCER BIOLOGY & THERAPY
卷 11, 期 2, 页码 263-276出版社
TAYLOR & FRANCIS INC
DOI: 10.4161/cbt.11.2.13959
关键词
ErbB2; Her2/Neu; 17-AAG; celastrol; trastuzumab; targeted therapy; drug interaction; ubiquitin; proteasome; HSP90; ROS
类别
资金
- NIH [CA116552, CA99163, CA87986, CA105489, CA94143, CA96844]
- DOD [DAMD W81XWH-07-1-0351, CA127239]
- Nebraska Department of Health and Human Services [LB-506]
- Nebraska Center for Nanomedicine-Center for Biomedical Research Excellence (NCN-COBRE)
- NCI [T32 CA 009476]
- Susan G. Komen Foundation [KG091363]
- Nebraska Research Initiative
- NCI Cancer Center [5 P30 CA036727]
The receptor tyrosine kinase ErbB2 is overexpressed in up to a third of breast cancers, allowing targeted therapy with ErbB2-directed humanized antibodies such as Trastuzumab. Concurrent targeting of ErbB2 stability with HSP 90 inhibitors is synergistic with Trastuzumab, suggesting that pharmacological agents that can inhibit HSP 90 as well as signaling pathways activated by ErbB2 could be useful against ErbB2-overexpressing breast cancers. The triterpene natural product Celastrol inhibits HSP 90 and several pathways relevant to ErbB2-dependent oncogenesis including the NF kappa B pathway and the proteasome, and has shown promising activity in other cancer models. Here, we demonstrate that Celastrol exhibits in vitro antitumor activity against a panel of human breast cancer cell lines with selectivity towards those overexpressing ErbB2. Celastrol strongly synergized with ErbB2-targeted therapeutics Trastuzumab and Lapatinib, producing higher cytotoxicity with substantially lower doses of Celastrol. Celastrol significantly retarded the rate of growth of ErbB2-overexpressing human breast cancer cells in a mouse xenograft model with only minor systemic toxicity. Mechanistically, Celastrol not only induced the expected ubiquitinylation and degradation of ErbB2 and other HSP 90 client proteins, but it also increased the levels of reactive oxygen species (ROS). Our studies show that the Michael Acceptor functionality in Celastrol is important for its ability to destabilize ErbB2 and exert its bioactivity against ErbB2-overexpressing breast cancer cells. These studies suggest the potential use of Michael acceptor-containing molecules as novel therapeutic modalities against ErbB2-driven breast cancer by targeting multiple biological attributes of the driver oncogene.
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