Antitumor activity of novel pyrazole-based small molecular inhibitors of the STAT3 pathway in patient derived high grade glioma cells

PloS One
Liang ZhangDavid J Daniels

Abstract

Abnormal activation of signal transducer and activator of transcription 3 (STAT3) transcription factor has been observed in many human cancers with roles in tumor initiation, progression, drug resistance, angiogenesis and immunosuppression. STAT3 is constitutively activated in a variety of cancers including adult high grade gliomas (aHGGs) such as glioblastoma (GBM), and pediatric high grade gliomas (pHGG). Inhibiting STAT3 is a promising target-specific chemotherapeutic strategy for tumors with aberrant STAT3 signaling. Here we investigated the antitumor effects of novel pyrazole-based STAT3 pathway inhibitors named MNS1 (Mayo Neurosurgery 1) in both pediatric and adult HGG tumor cells. MNS1 compounds selectively decreased cell viability and proliferation in patient-derived HGG cells with minimal toxicity on normal human astrocytes. These inhibitors selectively blocked IL-6-induced STAT3 phosphorylation and nuclear localization of pSTAT3 without affecting other signaling molecules including Akt, STAT1, JAK2 or ERK1/2 phosphorylation. Functional analysis showed that MNS1 compounds induced apoptosis and decrease tumor migration. The anti-tumor effects extended into a murine pHGG (diffuse intrinsic pontine glioma) patient derived...Continue Reading

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Citations

Mar 18, 2021·The Journal of Pharmacy and Pharmacology·Yaprak Dilber Şimay DemirMustafa Ark

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Methods Mentioned

BETA
nuclear translocation
FCS
Assay
protein
electrophoresis
scraping
flow cytometry
xenografts
xenograft
bioluminescence

Software Mentioned

GraphPad
LivingImage
Prism

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