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Mechanisms underlying the cytotoxicity of a novel quinazolinedione-based redox modulator, QD232, in pancreatic cancer cells

Pathania, Divya and Kuang, Yuting and Sechi, Mario and Neamati, Nouri (2015) Mechanisms underlying the cytotoxicity of a novel quinazolinedione-based redox modulator, QD232, in pancreatic cancer cells. British journal of pharmacology, Vol. 172 (1), p. 50-63. ISSN 0007-1188. eISSN 1476-5381. Article.

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DOI: 10.1111/bph.12855

Abstract

Background and Purpose
Pancreatic cancer is characterized by alterations in several key signalling proteins, including increased expression and activity of the Src tyrosine kinase and focal adhesion kinase (FAK), which have been linked to its chemoresistance. Sustained Src inhibition reactivates survival pathways regulated by the transcription factor STAT3, also leading to resistance. Therefore, simultaneously targeting Src/FAK and STAT3 signalling could provide an important strategy for treating pancreatic cancer. Recently, we described novel quinazolinediones that increased generation of reactive oxygen species (ROS) and were cytotoxic in pancreatic cancer cells. Here, we have investigated effects of our lead compound, QD232, on Src/FAK and STAT3 signalling.
Experimental Approach
The major signalling pathways affected by QD232 in pancreatic cancer cell lines were identified by Kinexus proteomic analysis. Changes in key signalling proteins were confirmed by Western blotting. Cell migration was assessed by Boyden chamber and wound healing assays. Direct inhibition of kinase activity in vitro was assayed with a panel of 92 oncogenic kinases. Safety and efficacy of QD232 were determined in a xenograft mouse model of pancreatic cancer.
Key Results
QD232 potently inhibited Src/FAK and STAT3 phosphorylation, decreasing pancreatic cancer cell viability and migration. Furthermore, QD232 arrested cell cycle progression and induced apoptosis in these cells at low micromolar concentrations. Effects of QD232 on Src/FAK and STAT3 phosphorylation were blocked by N-acetylcysteine or glutathione.
Conclusions and Implications
QD232 is a novel compound with a unique, ROS-dependent mechanism, effective in drug-resistant cancer cell lines. This compound shows potential as therapy for pancreatic cancer.

Item Type:Article
ID Code:10562
Status:Published
Refereed:Yes
Uncontrolled Keywords:Pancreatic cancer, focal adhesion kinase (FAK), oxygen species (ROS), QD232
Subjects:Area 03 - Scienze chimiche > CHIM/08 Chimica farmaceutica
Divisions:001 Università di Sassari > 01-a Nuovi Dipartimenti dal 2012 > Chimica e Farmacia
Publisher:Wiley
ISSN:0007-1188
eISSN:1476-5381
Copyright Holders:© 2014 The British Pharmacological Society
Deposited On:07 Jan 2015 18:02

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