A novel kinase inhibitor of FADD phosphorylation chemosensitizes through the inhibition of NF-κB.

Abstract

Fas-associated protein with death domain (FADD) is a cytosolic adapter protein essential for mediating death receptor-induced apoptosis. It has also been implicated in a number of nonapoptotic activities including embryogenesis, cell-cycle progression, cell proliferation, and tumorigenesis. Our recent studies have shown that high levels of phosphorylated FADD (p-FADD) in tumor cells correlate with increased activation of the antiapoptotic transcription factor NF-κB and is a biomarker for aggressive disease and poor clinical outcome. These findings suggest that inhibition of FADD phosphorylation is a viable target for cancer therapy. A high-throughput screen using a cell-based assay for monitoring FADD-kinase activity identified NSC 47147 as a small molecule inhibitor of FADD phosphorylation. The compound was evaluated in live cells and mouse tumors for its efficacy as an inhibitor of FADD-kinase activity through the inhibition of casein kinase 1α. NSC 47147 was shown to decrease levels of p-FADD and NF-κB activity such that combination therapy leads to greater induction of apoptosis and enhanced tumor control than either agent alone. The studies described here show the utility of bioluminescent cell-based assays for the identification of active compounds and the validation of drug-target interaction in a living subject. In addition, the presented results provide proof-of-principle studies as to the validity of targeting FADD-kinase activity as a novel cancer therapy strategy.

• Authors: Katrina A Schinske, Shyam Nyati, Amjad P Khan, Terence M Williams, Timothy D Johnson, Brian D Ross, Ricardo Pérez Tomás, Alnawaz Rehemtulla
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 10 Issue 10 Pg. 1807-17 (Oct 2011) ISSN: 1538-8514 [Electronic] United States
• PMID: 21859840 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Alkaloids
• FADD protein, human
• Fas-Associated Death Domain Protein
• NF-kappa B
• Protein Kinase Inhibitors
• Pyrroles
• Transcription Factors
• Cisplatin

Topics

• Alkaloids (pharmacology)
• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cisplatin (administration & dosage, pharmacology)
• Fas-Associated Death Domain Protein (antagonists & inhibitors, metabolism)
• Humans
• Jurkat Cells
• Male
• Mice
• Mice, Nude
• NF-kappa B (antagonists & inhibitors, metabolism)
• Phosphorylation (drug effects)
• Protein Kinase Inhibitors (administration & dosage, pharmacology)
• Pyrroles (pharmacology)
• Random Allocation
• Transcription Factors (metabolism)
• Xenograft Model Antitumor Assays