A Brain-Penetrating Hsp90 Inhibitor NXD30001 Inhibits Glioblastoma as a Monotherapy or in Combination With Radiation

作者：Hao Chen, Yuanying Gong, Yufang Ma, Reid C. Thompson, Jialiang Wang, Zhixiang Cheng, Lixia Xue · 发表于：Frontiers in Pharmacology · 年份：2020 · DOI：10.3389/fphar.2020.00974 · 被引用次数：25 · 研究领域：Heat shock proteins research、Endoplasmic Reticulum Stress and Disease、Effects of Radiation Exposure

Glioblastoma multiforme (GBM) is a highly heterogeneous disease, which is initiated and sustained by various molecular alterations in an array of signal transduction pathways. Heat-shock protein 90 (Hsp90) is a molecular chaperone and is critically implicated in folding and activation of a diverse group of client proteins, many of which are key regulators for glioblastoma biology. We here assessed the anti-neoplastic efficacy of a novel brain-penetrating Hsp90 inhibitor NXD30001 as a monotherapy and combined with radiation in vitro and in vivo. Our results demonstrated that NXD30001 potently inhibited neurosphere formation, growth and survival of CD133+ GBM cells with the half maximal inhibitory concentration at low nanomolar range, but CD133- GBM cells were less sensitive to NXD30001. NXD30001 also increased radio-sensitivity in glioblastoma stem cells (GSCs) at suboptimal concentrations. Moreover, NXD30001 dose-dependently decreased phosphorylation levels of multiple Hsp90 client proteins which play key roles in GBM, such as EGFR, Akt, c-Myc and Notch1. In addition, NXD30001 could impair DNA damage response and endoplasmic reticulum stress response after radiotherapy by alteration of the related proteins expression. In a murine orthotopic model of human glioblastoma, NXD30001 marvelously induced tumor regression and extended median survival of tumor-bearing mice by approximately 20% when compared with the vehicle group (37 days vs 31 days, P<0.05). Radiotherapy solely incre...