Ebselen inhibits QSOX1 enzymatic activity and suppresses invasion of pancreatic and renal cancer cell lines.

Abstract

Quiescin sulfhydryl oxidase 1 (QSOX1) is a highly conserved disulfide bond-generating enzyme that is overexpressed in diverse tumor types. Its enzymatic activity promotes the growth and invasion of tumor cells and alters extracellular matrix composition. In a nude mouse-human tumor xenograft model, tumors containing shRNA for QSOX1 grew significantly more slowly than controls, suggesting that QSOX1 supports a proliferative phenotype in vivo. High throughput screening experiments identified ebselen as an in vitro inhibitor of QSOX1 enzymatic activity. Ebselen treatment of pancreatic and renal cancer cell lines stalled tumor growth and inhibited invasion through Matrigel in vitro. Daily oral treatment with ebselen resulted in a 58% reduction in tumor growth in mice bearing human pancreatic tumor xenografts compared to controls. Mass spectrometric analysis of ebselen-treated QSOX1 mechanistically revealed that C165 and C237 of QSOX1 covalently bound to ebselen. This report details the anti-neoplastic properties of ebselen in pancreatic and renal cancer cell lines. The results here offer a "proof-of-principle" that enzymatic inhibition of QSOX1 may have clinical relevancy.

• Authors: Paul D Hanavan, Chad R Borges, Benjamin A Katchman, Douglas O Faigel, Thai H Ho, Chen-Ting Ma, Eduard A Sergienko, Nathalie Meurice, Joachim L Petit, Douglas F Lake
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 21 Pg. 18418-28 (Jul 30 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26158899 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Azoles
• Isoindoles
• Organoselenium Compounds
• ebselen
• Oxidoreductases Acting on Sulfur Group Donors
• QSOX1 protein, human
• Cysteine

Topics

• Amino Acid Sequence
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (chemistry, pharmacology)
• Azoles (chemistry, pharmacology)
• Blotting, Western
• Carcinoma, Renal Cell (drug therapy, genetics, metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects, genetics)
• Cysteine (antagonists & inhibitors, genetics, metabolism)
• Humans
• Isoindoles
• Kidney Neoplasms (drug therapy, genetics, metabolism)
• Mice, Nude
• Molecular Sequence Data
• Molecular Structure
• Neoplasm Invasiveness
• Organoselenium Compounds (chemistry, pharmacology)
• Oxidoreductases Acting on Sulfur Group Donors (antagonists & inhibitors, genetics, metabolism)
• Pancreatic Neoplasms (drug therapy, genetics, metabolism)
• RNA Interference
• Sequence Homology, Amino Acid
• Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
• Tumor Burden (drug effects, genetics)
• Xenograft Model Antitumor Assays