Glioblastoma invasion, cathepsin B, and the potential for both to be inhibited by auranofin, an old anti-rheumatoid arthritis drug.

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.