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DOI: 10.1055/s-0029-1242756
© Georg Thieme Verlag KG Stuttgart · New York
Glioblastoma Invasion, Cathepsin B, and the Potential for Both to be Inhibited by Auranofin, an Old Anti-Rheumatoid Arthritis Drug
Publikationsverlauf
Publikationsdatum:
01. Februar 2010 (online)
![](https://www.thieme-connect.de/media/zblneurochir/201003/lookinside/thumbnails/10.1055-s-0029-1242756-1.jpg)
Abstract
Cathepsin B activity is absent in normal brain tissue but overexpressed in glioblastomas. Immunohistochemistry localizes cathepsin B to areas of invasion and neovascularization. Several research teams have confirmed the relationship between higher cathepsin B expression, more aggressive glioblastoma course and a shorter overall survival. An old anti-rheumatoid arthritis drug, auranofin, has a documented micromolar range for the inhibition of cathepsin B. Such levels are clinically achievable with the adequately tolerated doses that are used to treat rheumatoid arthritis. The side-effect profile of auranofin, although not entirely problem-free, is benign enough to warrant further trials in good fidelity rodent glioblastoma models followed by a translation to clinical trials if these confirm a potential for benefit. A newly discovered amplification loop between cathepsin B and urokinase-type plasminogen activator outlined in this paper is active in glioblastoma and makes auranofin inhibition particularly attractive for its potential to inhibit the matrix degrading feedback cycle.
Key words
auranofin - cathepsin B - extracellular matrix - glioblastoma - urokinase
References
- 1 Lefranc F, Sadeghi N, Camby I. et al . Present and potential future issues in glioblastoma treatment. Expert Rev Anticancer Ther. 2006; 6 (5) 719-732
- 2 Hayashi Y, Edwards NA, Proescholdt MA. et al . Regulation and function of aquaporin-1 in glioma cells. Neoplasia. 2007; 9 777-787
- 3 Strojnik T, Kavalar R, Trinkaus M. et al . Cathepsin L in glioma progression: comparison with cathepsin B. Cancer Detect Prev. 2005; 29 448-455
- 4 Wang M, Tang J, Liu S. et al . Expression of cathepsin B and microvascular density increases with higher grade of astrocytomas. J Neurooncol. 2005; 71 3-7
- 5 Gondi CS, Lakka SS, Yanamandra N. et al . Adenovirus-mediated expression of antisense urokinase plasminogen activator receptor and antisense cathepsin B inhibits tumor growth, invasion, and angiogenesis in gliomas. Cancer Res. 2004; 64 4069-4077
- 6 Mai J, Sameni M, Mikkelsen T. et al . Degradation of extracellular matrix protein tenascin-C by cathepsin B: an interaction involved in the progression of gliomas. Biol Chem. 2002; 383 1407-1413
- 7 Strojnik T, Zajc I, Bervar A. et al . Cathepsin B and its inhibitor stefin A in brain tumors. Pflugers Arch. 2000; 439 (3 Suppl) R122-R123
- 8 Strojnik T, Kos J, Zidanik B. et al . Cathepsin B immunohistochemical staining in tumor and endothelial cells is a new prognostic factor for survival in patients with brain tumors. Clin Cancer Res. 1999; 5 559-567
- 9 Mikkelsen T, Yan PS, Ho KL. et al . Immunolocalization of cathepsin B in human glioma: implications for tumor invasion and angiogenesis. J Neurosurg. 1995; 83 285-290
- 10 Colin C, Voutsinos-Porche B,, Nanni I. et al . High expression of cathepsin B and plasminogen activator inhibitor type-1 are strong predictors of survival in glioblastomas. Acta Neuropathol. 2009 Sept 23; [Epub ahead of print] PubMed PMID: 19774387
- 11 Rempel SA, Rosenblum ML, Mikkelsen T. et al . Cathepsin B expression and localization in glioma progression and invasion. Cancer Res. 1994; 54 6027-6031
- 12 Yamamoto M, Ueno Y, Hayashi S. et al . The role of proteolysis in tumor invasiveness in glioblastoma and metastatic brain tumors. Anticancer Res. 2002; 22 4265-4268
- 13 Levicar N, Nuttall RK, Lah TT. Proteases in brain tumour progression. Acta Neurochir (Wien). 2003; 145 825-838
- 14 Lakka SS, Gondi CS, Yanamandra N. et al . Inhibition of cathepsin B and MMP-9 gene expression in glioblastoma cell line via RNA interference reduces tumor cell invasion, tumor growth and angiogenesis. Oncogene. 2004; 23 4681-4689
- 15 Yanamandra N, Gumidyala KV, Waldron KG. et al . Blockade of cathepsin B expression in human glioblastoma cells is associated with suppression of angiogenesis. Oncogene. 2004; 23 2224-2230
- 16 Konduri SD, Yanamandra N, Siddique K. et al . Modulation of cystatin C expression impairs the invasive and tumorigenic potential of human glioblastoma cells. Oncogene. 2002; 21 8705-8712
- 17 Mohanam S, Jasti SL, Kondraganti SR. et al . Down-regulation of cathepsin B expression impairs the invasive and tumorigenic potential of human glioblastoma cells. Oncogene. 2001; 20 3665-3673
- 18 Werle B, Ebert W, Klein W. et al . Cathepsin B in tumors, normal tissue and isolated cells from the human lung. Anticancer Res. 1994; 14 1169-1176
- 19 Iwatsuki K, Kumara E, Yoshimine T. et al . Elastase expression by infiltrating neutrophils in gliomas. Neurol Res. 2000; 22 (5) 465-468
- 20 Kean WF, Hart L, Buchanan WW. Auranofin. Br J Rheumatol. 1997; 36 560-572
- 21 Gunatilleke SS, de Oliveira CA, McCammon JA. et al . Inhibition of cathepsin B by Au(I) complexes: a kinetic and computational study. J Biol Inorg Chem. 2008; 13 555-561
- 22 Gunatilleke SS, Barrios AM. Tuning the Au(I)-mediated inhibition of cathepsin B through ligand substitutions. J Inorg Biochem. 2008; 102 555-563
- 23 Cox AG, Brown KK, Arner ES. et al . The thioredoxin reductase inhibitor auranofin triggers apoptosis through a Bax/Bak-dependent process that involves peroxiredoxin 3 oxidation. Biochem Pharmacol. 2008; 76 1097-1109
- 24 Talbot S, Nelson R, Self WT. Arsenic trioxide and auranofin inhibit selenoprotein synthesis: implications for chemotherapy for acute promyelocytic leukaemia. Br J Pharmacol. 2008; 154 940-948
- 25 Becker K, Gromer S, Schirmer RH. et al . Thioredoxin reductase as a pathophysiological factor and drug target. Eur J Biochem. 2000; 267 6118-6125
- 26 Marzano C, Gandin V, Folda A. et al . Inhibition of thioredoxin reductase by auranofin induces apoptosis in cisplatin-resistant human ovarian cancer cells. Free Radic Biol Med. 2007; 42 872-881
- 27 Tiekink ER. Anti-cancer potential of gold complexes. Inflammopharmacology. 2008; 16 138-142
- 28 Inubushi T, Okada M, Matsui A. et al . Effect of dietary vitamin B6 contents on antibody production. Biofactors. 2000; 11 93-96
- 29 Katunuma N, Matsui A, Endo K. et al . Inhibition of intracellular cathepsin activities and suppression of immune responses mediated by helper T lymphocyte type-2 by peroral or intraperitoneal administration of vitamin B. Biochem Biophys Res Commun. 2000; 272 151-155
- 30 Katunuma N, Matsunaga Y, Matsui A. et al . Novel physiological functions of cathepsins B and L on antigen processing and osteoclastic bone resorption. Adv Enzyme Regul. 1998; 38 235-251
- 31 Snodgrass SR. Vitamin neurotoxicity. Mol Neurobiol. 1992; 6 41-73
- 32 Guo M, Mathieu PA, Linebaugh B. et al . Phorbol ester activation of a proteolytic cascade capable of activating latent transforming growth factor-beta. A process initiated by the exocytosis of cathepsin B. J Biol Chem. 2002; 277 14829-14837
- 33 Kobayashi H, Moniwa N, Sugimura M. et al . Effects of membrane-associated cathepsin B on the activation of receptor-bound pro-urokinase and subsequent invasion of reconstituted basement membranes. Biochim Biophys Acta. 1993; 1178 55-62
- 34 Salajegheh M, Rudnicki A, Smith TW. Expression of urokinase-type plasminogen activator receptor (uPAR) in primary central nervous system neoplasms. Appl Immunohistochem Mol Morphol. 2005; 13 184-189
- 35 Zhao Y, Lyons Jr CE, Xiao A. et al . Urokinase directly activates matrix metalloproteinases-9: a potential role in glioblastoma invasion. Biochem Biophys Res Commun. 2008; 369 1215-1220
- 36 Gole B, Durán Alonso MB, Dolenc V. et al . Post-translational regulation of cathepsin B, but not of other cysteine cathepsins, contributes to increased glioblastoma cell invasiveness in vitro. Pathol Oncol Res. 2009 May; 13 [Epub ahead of print] PMID: 19434518
- 37 Kast RE. Why cerebellar glioblastoma is rare and how that indicates adjunctive use of the FDA-approved anti-emetic aprepitant might retard cerebral glioblastoma growth: a new hypothesis to an old question. Clin Transl Oncol. 2009; 11 (7) 408-410
- 38 Kast RE, Belda-Iniesta C. Suppressing glioblastoma stem cell function by aldehyde dehydrogenase inhibition with chloramphenicol or disulfiram as a new treatment adjunct: An hypothesis. Curr Stem Cell Res Ther. 2009 Dec; 1 [Epub ahead of print] PubMed PMID: 19500061
- 39 Kast RE, Altschuler EL. Current drugs available now for interleukin-6 suppression as treatment adjunct in glioblastoma: anakinra, aprepitant, mirtazapine and olanzapine. Int J Cancer Res. 2006; 2 303-314
- 40 Kuhn SA, Mueller U, Hanisch UK. et al . Glioblastoma cells express functional cell membrane receptors activated by daily used medical drugs. J Cancer Res Clin Oncol. 2009 Jun; 19 PubMed PMID: 19543745
- 41 Carapancea M, Alexandru O, Fetea AS. et al . Growth factor receptors signaling in glioblastoma cells: therapeutic implications. J Neurooncol. 2009; 92 (2) 137-147
Correspondence
Dr. R. E. Kast
University of Vermont Psychiatry
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United States
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