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

Frontiers in Pharmacology
Hao ChenLixia Xue

Abstract

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 mu...Continue Reading

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Citations

Dec 29, 2020·Biochimica Et Biophysica Acta. Molecular Cell Research·Abhijnya Kanugovi Vijayavittal, Sreedhar Amere Subbarao
Feb 12, 2021·Brain Disorders·Mohammad A UddinNektarios Barabutis

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Methods Mentioned

BETA
surgical resection
xenograft
X-ray
Assay
protein assay
electrophoreses
bioluminescence imaging
flow cytometry
irradiate

Software Mentioned

GraphPad
Living Image
GraphPad Prism5
BD
GraphPad Prism

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