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.

Mass spectrometry‐based secretome analysis of non‐small cell lung cancer cell lines

“…Furthermore, QSOX 1 expression levels seem to be correlated with patient prognosis in breast cancer . As such, QSOX 1 is an emerging target in tumor biology and recent reports indicate that invasion of cancer cells can be suppressed by inhibiting its enzymatic activity .…”

Ebselen as a highly active inhibitor of PLProCoV2

“…Ebselen is a low-molecular-weight organoselenium drug that shows pleiotropic mode of action and due to its very low toxicity there are no barriers to using it in humans [15]. It is a well-known agent with therapeutic activity in neurological disorders [16] and cancers [17]. It also showed an antiviral effect on neurotropic viruses [18] and hepatitis C virus [19].…”

Newly-presented potential targeted drugs in the treatment of renal cell cancer

“…QSOX1 promotes the growth and invasion of caner cells and influences extracellular matrix composition. Hanavan et al [21] had report that, after mass spectrometric analysis of ebselentreated QSOX1, they found that the C165 and C237 of QSOX1 covalently bound to ebselen. Their study depicts the anti-neoplastic properties of ebselen in renal cancer cell lines, providing a "proof-of-principle" that enzymatic inhibitorry of QSOX1 may have clinical benefits.…”