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Clioquinol inhibits the proteasome and displays preclinical activity in leukemia and myeloma

Leukemia volume 23, pages 585–590 (2009)Cite this article

The 26S proteasome comprises the 19S proteasome that performs a regulatory function, and the 20S proteasome that is responsible for the enzymatic degradation of proteins. The 20S proteasome comprises α- and β-subunits that form the outer and inner rings of this complex, respectively.1 The α-subunits form an antechamber that gives the proteasome its barrel shape and regulates the flow of substrates into the proteolytic chamber in the center of the barrel.1 The β-subunits form the proteolytic chamber of the 20S proteasome and perform the peptidase function of the complex.1 Bortezomib (Velcade) is an intravenous proteasome inhibitor that is approved for the treatment of multiple myeloma and mantle cell lymphoma.2, 3 Mechanistically, Bortezomib binds the active sites of the enzymes in the β-subunits located in the proteolytic chamber of the 20S proteasome.4 Molecules that inhibit the proteasome through a different mechanism would be useful probes to understand the activity of this enzyme complex and potentially new therapeutic agents.

LP-1 and OCI-MY5 myeloma cell lines were treated with increasing concentrations of clioquinol, and 24 h after treatment the abundance of ubiquitinated proteins in the cells was measured by immunoblotting. At low micromolar concentrations, clioquinol increased the amount of ubiquitinated proteins, and copper supplementation of the media was not required to observe this effect (Figure 1b). To assess the spectrum of activity of clioquinol as a proteasome inhibitor, we examined the effects of clioquinol on the activity of the chymotrypsin-like proteasomal enzyme in cell lines and primary patient samples. Leukemia, myeloma and solid tumor cell lines were treated with increasing concentration of clioquinol for 24 h. After treatment, cells were harvested and lysed, and the chymotrypsin-like activity of the proteasome was measured by monitoring the rate of cleavage of the fluorescent substrate Suc-LLVY-AMC (Figure 1c). Clioquinol inhibited the rate of Suc-LLVY-AMC cleavage in myeloma and leukemia cell lines but not in the tested solid tumor cells. Thus, the results in leukemia and myeloma cells are different than in solid tumor lines, where, consistent with previous reports, clioquinol is ineffective without copper supplementation.5

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References

  1. Lowe J, Stock D, Jap B, Zwickl P, Baumeister W, Huber R . Crystal structure of the 20S proteasome from the archaeon T. acidophilum at 3.4 A resolution. Science 1995; 268: 533–539.

    Article  CAS  Google Scholar 

  2. Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005; 352: 2487–2498.

    Article  CAS  Google Scholar 

  3. Fisher RI, Bernstein SH, Kahl BS, Djulbegovic B, Robertson MJ, de Vos S et al. Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. J Clin Oncol 2006; 24: 4867–4874.

    Article  Google Scholar 

  4. Groll M, Berkers CR, Ploegh HL, Ovaa H . Crystal structure of the boronic acid-based proteasome inhibitor bortezomib in complex with the yeast 20S proteasome. Structure 2006; 14: 451–456.

    Article  CAS  Google Scholar 

  5. Chen D, Cui QC, Yang H, Barrea RA, Sarkar FH, Sheng S et al. Clioquinol, a therapeutic agent for Alzheimer's disease, has proteasome-inhibitory, androgen receptor-suppressing, apoptosis-inducing, and antitumor activities in human prostate cancer cells and xenografts. Cancer Res 2007; 67: 1636–1644.

    Article  CAS  Google Scholar 

  6. Sprangers R, Li X, Mao X, Rubinstein JL, Schimmer AD, Kay LE . TROSY-based NMR evidence for a novel class of 20S proteasome inhibitors. Biochemistry 2008; 112: 760–769.

    Google Scholar 

  7. Ritchie CW, Bush AI, Mackinnon A, Macfarlane S, Mastwyk M, MacGregor L et al. Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial. Arch Neurol 2003; 60: 1685–1691.

    Article  Google Scholar 

  8. Tateishi J . Subacute myelo-optico-neuropathy: clioquinol intoxication in humans and animals. Neuropathology 2000; 20 (Suppl): S20–S24.

    Article  Google Scholar 

Download references

Acknowledgements

This study was supported with funding from the Multiple Myeloma Research Foundation, The Princess Margaret Hospital Foundation, the Ontario Institute for Cancer Research through the Ministry of Research and Innovation, and the Leukemia and Lymphoma Society.

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Author notes

  1. X Mao and X Li: These authors contributed equally to this study.

Authors and Affiliations

  1. Department of Cancer Genomics and Proteomics, Ontario Cancer Institute, Princess Margaret Hospital, Toronto, ON, Canada

    X Mao, X Li, X Wang, A Venugopal, T Wood, Y Zhang, D A Kuntz, E Coe, S Trudel, D Rose & A D Schimmer

  2. Department of Medical Genetics, The University of Toronto, Toronto, ON, Canada

    R Sprangers & L E Kay

  3. Department of Biochemistry, The University of Toronto, Toronto, ON, Canada

    R Sprangers

  4. Department of Chemistry, The University of Toronto, Toronto, ON, Canada

    R Sprangers

  5. Department of Chemistry, The University of Toronto, Toronto, ON, Canada

    T Wood, Y Zhang & R A Batey

  6. Department of Medical Biophysics, The University of Toronto, Toronto, ON, Canada

    S Trudel, D Rose & A D Schimmer

  7. Department of Medicine, The University of Toronto, Toronto, ON, Canada

    S Trudel & A D Schimmer

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  1. X Mao
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Correspondence to A D Schimmer.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Mao, X., Li, X., Sprangers, R. et al. Clioquinol inhibits the proteasome and displays preclinical activity in leukemia and myeloma. Leukemia 23, 585–590 (2009). https://doi.org/10.1038/leu.2008.232

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