A screen for drugs that protect against the cytotoxicity of polyglutamine-expanded androgen receptor.
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.
Piccioni
Federica
F
Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MS 20892-1250, USA.
Roman
Benjamin R
BR
Fischbeck
Kenneth H
KH
Taylor
J Paul
JP
D017209:Apoptosis / Q000187:drug effects*; D015220:Calcium Channels / Q000187:drug effects; D002298:Cardenolides / Q000494:pharmacology; D053148:Caspase 3; D020169:Caspases; D002478:Cells, Cultured; D004074:Digitoxin / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D020966:Muscular Disorders, Atrophic / Q000235:genetics*; D009154:Mutation; D010455:Peptides / Q000737:chemistry*; D011944:Receptors, Androgen / Q000235:genetics*; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors; D013468:Suloctidil / Q000494:pharmacology; D018911:Trinucleotide Repeats / Q000235:genetics
D015220:Calcium Channels; D002298:Cardenolides; D004791:Enzyme Inhibitors; D010455:Peptides; D011944:Receptors, Androgen; C097188:polyglutamine; C040684:neriifolin; C100098:cannogenin thevetoside; D004074:Digitoxin; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D000254:Sodium-Potassium-Exchanging ATPase; D013468:Suloctidil