title: Progesterone receptor chaperone complex-based high-throughput screening assay: identification of capsaicin as an inhibitor of the Hsp90 machine.
abstract: Hsp90 and its co-chaperones are known to be important for cancer cell survival. The N-terminal inhibitors of Hsp90 that are in ongoing clinical trials as antitumor agents have unfortunately shown disappointing efficacies in the clinic. Thus, novel inhibitors of the Hsp90 machine with a different mechanism of action are urgently needed. We report here the development of a novel high-throughput screening assay platform to identify small-molecule inhibitors of Hsp90 and its co-chaperones. This assay quantitatively measures the ability of Hsp90 and its co-chaperones to refold/protect the progesterone receptor, a physiological client of Hsp90, in a 96-well plate format. We screened the National Institutes of Health clinical collection drug library and identified capsaicin as a hit molecule. Capsaicin is a Food and Drug Administration-approved drug for topical use in pain management. Cell survival assays showed that capsaicin selectively kills cancer cells and destabilizes several Hsp90 client proteins. Thus, our data may explain the seemingly pleotropic effect of capsaicin.
authors.affiliation: GRU Cancer Center, Molecular Chaperones Group, Georgia Regents University, Augusta, GA, USA.
authors.forename: Chaitanya A
authors.initials: CA
authors.lastname: Patwardhan
authors.affiliation: GRU Cancer Center, Molecular Chaperones Group, Georgia Regents University, Augusta, GA, USA.
authors.forename: Eyad
authors.initials: E
authors.lastname: Alfa
authors.affiliation: GRU Cancer Center, Molecular Chaperones Group, Georgia Regents University, Augusta, GA, USA.
authors.forename: Su
authors.initials: S
authors.lastname: Lu
authors.affiliation: GRU Cancer Center, Molecular Chaperones Group, Georgia Regents University, Augusta, GA, USA achadli@gru.edu.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Chadli
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002211:Capsaicin / Q000494:pharmacology; D055808:Drug Discovery / Q000379:methods*; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D018832:Molecular Chaperones / Q000378:metabolism*; D011485:Protein Binding; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D015203:Reproducibility of Results; D054852:Small Molecule Libraries
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D018832:Molecular Chaperones; D011980:Receptors, Progesterone; D054852:Small Molecule Libraries; D002211:Capsaicin
keywords: Hsp90 machine; capsaicin; high-throughput screening assay; molecular chaperones; progesterone receptor