A novel proteasome inhibitor suppresses tumor growth via targeting both 19S proteasome deubiquitinases and 20S proteolytic peptidases

Sci Rep. 2014 Jun 10;4:5240. doi: 10.1038/srep05240.

Abstract

The successful development of bortezomib-based therapy for treatment of multiple myeloma has established proteasome inhibition as an effective therapeutic strategy, and both 20S proteasome peptidases and 19S deubiquitinases (DUBs) are becoming attractive targets of cancer therapy. It has been reported that metal complexes, such as copper complexes, inhibit tumor proteasome. However, the involved mechanism of action has not been fully characterized. Here we report that (i) copper pyrithione (CuPT), an alternative to tributyltin for antifouling paint biocides, inhibits the ubiquitin-proteasome system (UPS) via targeting both 19S proteasome-specific DUBs and 20S proteolytic peptidases with a mechanism distinct from that of the FDA-approved proteasome inhibitor bortezomib; (ii) CuPT potently inhibits proteasome-specific UCHL5 and USP14 activities; (iii) CuPT inhibits tumor growth in vivo and induces cytotoxicity in vitro and ex vivo. This study uncovers a novel class of dual inhibitors of DUBs and proteasome and suggests a potential clinical strategy for cancer therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Boronic Acids / pharmacology
  • Bortezomib
  • Cell Line
  • Cell Line, Tumor
  • HEK293 Cells
  • Hep G2 Cells
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Multiple Myeloma / drug therapy
  • Multiple Myeloma / metabolism
  • Organometallic Compounds / pharmacology
  • Peptide Hydrolases / metabolism*
  • Protease Inhibitors / pharmacology
  • Proteasome Endopeptidase Complex / metabolism*
  • Proteasome Inhibitors / pharmacology*
  • Proteolysis / drug effects*
  • Pyrazines / pharmacology
  • Pyridines / pharmacology
  • Ubiquitin / metabolism
  • Ubiquitin-Specific Proteases / metabolism*

Substances

  • Antineoplastic Agents
  • Boronic Acids
  • Organometallic Compounds
  • Protease Inhibitors
  • Proteasome Inhibitors
  • Pyrazines
  • Pyridines
  • Ubiquitin
  • copper pyrithione
  • Bortezomib
  • Peptide Hydrolases
  • Ubiquitin-Specific Proteases
  • Proteasome Endopeptidase Complex