Department of Medicine, Evanston Northwestern Healthcare Research Institute, Northwestern University, Evanston, IL, USA.
Cancer Biol Ther. 2011 Jan 15;11(2):263-76. doi: 10.4161/cbt.11.2.13959.
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 HSP90 inhibitors is synergistic with Trastuzumab, suggesting that pharmacological agents that can inhibit HSP90 as well as signaling pathways activated by ErbB2 could be useful against ErbB2-overexpressing breast cancers. The triterpene natural product Celastrol inhibits HSP90 and several pathways relevant to ErbB2-dependent oncogenesis including the NFκB 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 HSP90 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.
受体酪氨酸激酶 ErbB2 在多达三分之一的乳腺癌中过表达，这使得可以使用针对 ErbB2 的人源化抗体（如曲妥珠单抗）进行靶向治疗。同时使用 HSP90 抑制剂靶向 ErbB2 稳定性与曲妥珠单抗具有协同作用，这表明可以抑制 HSP90 以及由 ErbB2 激活的信号通路的药理制剂可能对 ErbB2 过表达的乳腺癌有用。三萜天然产物 Celastrol 抑制 HSP90 和与 ErbB2 依赖性致癌作用相关的几种途径，包括 NFκB 途径和蛋白酶体，并且在其他癌症模型中显示出有希望的活性。在这里，我们证明 Celastrol 对一组人乳腺癌细胞系具有体外抗肿瘤活性，对过表达 ErbB2 的细胞具有选择性。Celastrol 与 ErbB2 靶向治疗药物曲妥珠单抗和拉帕替尼强烈协同作用，使用 Celastrol 的剂量大大降低，产生更高的细胞毒性。Celastrol 显著延缓了在荷瘤小鼠模型中过表达 ErbB2 的人乳腺癌细胞的生长速度，而全身毒性较小。从机制上讲，Celastrol 不仅诱导了预期的 ErbB2 和其他 HSP90 客户蛋白的泛素化和降解，而且还增加了活性氧（ROS）的水平。我们的研究表明，Celastrol 中的迈克尔受体功能对于其不稳定 ErbB2 并发挥其针对过表达 ErbB2 的乳腺癌细胞的生物活性很重要。这些研究表明，含有迈克尔受体的分子可能通过针对驱动致癌基因的多种生物学特性，作为针对 ErbB2 驱动的乳腺癌的新型治疗方式。
