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Human Molecular Genetics Advance Access originally published online on January 6, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 4 437-446
DOI: 10.1093/hmg/ddh045

A screen for drugs that protect against the cytotoxicity of polyglutamine-expanded androgen receptor

Federica Piccioni1, Benjamin R. Roman1, Kenneth H. Fischbeck1 and J. Paul Taylor1,2,*

1Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-1250, USA and 2University of Pennsylvania School of Medicine, Department of Neurology, Philadelphia, PA 19104, USA

Received October 21, 2003; Accepted December 17, 2003

Spinobulbar muscular atrophy is a neurodegenerative disorder caused by expansion of a CAG triplet repeat sequence encoding a polyglutamine tract in the androgen receptor. It has been shown that the mutant protein is toxic in cell culture and triggers an apoptotic cascade resulting in activation of caspase-3. We developed an assay of caspase-3 activation in cells expressing the mutant androgen receptor. This assay was used to screen 1040 drugs, most of which are approved for clinical use. Drugs that inhibit polyglutamine-dependent activation of caspase-3 were subjected to follow-up screens to identify compounds that reproducibly prevent polyglutamine-induced cytotoxicity. Four drugs satisfied these criteria. Three of these (digitoxin, nerifolin and peruvoside) are structurally and functionally related compounds of the cardiac glycoside class and known inhibitors of Na+K+-ATPase. The fourth compound, suloctidil, is a calcium channel blocker.

* To whom correspondence should be addressed at: Department of Neurology, University of Pennsylvania School of Medicine, 3 West Gates Building, 3400 Spruce St, Philadelphia, PA 19104, USA. Tel: +1 2155731147; Fax: +1 2155731153; Email: jpt{at}mail.med.upenn.edu


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