期刊
MOLECULAR CANCER RESEARCH
卷 19, 期 7, 页码 1137-1145出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-21-0099
关键词
-
资金
- U.S. Department of Defense (DOD) Idea Award [W81XWH-19-1-0564]
NF-kappa B activation is linked to prostate cancer progression and resistance to androgen-deprivation therapy, suggesting the potential of NF-kappa B inhibitors to prevent resistance. Dimethylaminoparthenolide (DMAPT) shows promise as an oral NF-kappa B inhibitor, reducing NF-kappa B levels and enhancing AR inhibition in prostate cancer cells.
NF-kappa B activation has been linked to prostate cancer progression and is commonly observed in castrate-resistant disease. It has been suggested that NF-kappa B-driven resistance to androgen-deprivation therapy (ADT) in prostate cancer cells may be mediated by aberrant androgen receptor (AR) activation and AR splice variant production. Preventing resistance to ADT may therefore be achieved by using NF-kappa B inhibitors. However, low oral bioavailability and high toxicity of NF-kappa B inhibitors is a major challenge for clinical translation. Dimethylaminoparthenolide (DMAPT) is an oral NF-kappa B inhibitor in clinical development and has already shown favorable pharmacokinetic and pharmacodyanamic data in patients with heme malignancies, including decrease of NF-kappa B in circulating leuchemic blasts. Here, we report that activation of NF-kappa B/p65 by castration in mouse and human prostate cancer models resulted in a significant increase in AR variant-7 (AR-V7) expression and modest upregulation of AR. In vivo castration of VCAP-CR tumors resulted in significant upregulation of phosphorylated-p65 and AR-V7, which was attenuated by combination with DMAPT and DMAPT increased the efficacy of AR inhibition. We further demonstrate that the effects of DMAPT-sensitizing prostate cancer cells to castration were dependent on the ability of DM APT to inhibit phosphorylated-p65 function.
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