suloctidil and cannogenin-thevetoside

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.

Topics: Apoptosis; Calcium Channels; Cardenolides; Caspase 3; Caspases; Cells, Cultured; Digitoxin; Drug Evaluation, Preclinical; Enzyme Inhibitors; Humans; Muscular Disorders, Atrophic; Mutation; Peptides; Receptors, Androgen; Sodium-Potassium-Exchanging ATPase; Suloctidil; Trinucleotide Repeats