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

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.

• Authors: Divya Pathania, Yuting Kuang, Mario Sechi, Nouri Neamati
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 172 Issue 1 Pg. 50-63 (Jan 2015) ISSN: 1476-5381 [Electronic] England
• PMID: 25047070 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 The British Pharmacological Society.

Chemical References

• 6-((3-acetylphenyl)amino)quinazoline-5,8-dione
• Aniline Compounds
• Antineoplastic Agents
• Protein Kinase Inhibitors
• Quinazolinones
• Reactive Oxygen Species
• STAT3 Transcription Factor
• STAT3 protein, human
• Focal Adhesion Protein-Tyrosine Kinases
• src-Family Kinases

Topics

• Aniline Compounds (pharmacology, therapeutic use)
• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Cell Cycle (drug effects)
• Cell Line
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Survival (drug effects)
• Female
• Focal Adhesion Protein-Tyrosine Kinases (antagonists & inhibitors, metabolism)
• Humans
• Mice, Nude
• Pancreatic Neoplasms (drug therapy, metabolism, pathology)
• Phosphorylation (drug effects)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Quinazolinones (pharmacology, therapeutic use)
• Reactive Oxygen Species (metabolism)
• STAT3 Transcription Factor (antagonists & inhibitors, metabolism)
• Tumor Burden (drug effects)
• Wound Healing (drug effects)
• Xenograft Model Antitumor Assays
• src-Family Kinases (antagonists & inhibitors, metabolism)