title: How Selective are Hsp90 Inhibitors for Cancer Cells over Normal Cells?
abstract: Selectively inhibiting target proteins in cancer cells over normal cells is one of the most critical features of a successful protein inhibitor for clinical applications. By evaluating and comparing the impact of a clinical N-terminal heat shock protein 90 (Hsp90) inhibitor, AUY922 (luminespib), on Hsp90 inhibition-associated cellular events in cancer cells versus normal cells, we found that it produces similar phenotype characteristics in both cell types, indicating that AUY922 is not selective for targeting Hsp90 in tumor cells. By comparison, the C-terminal Hsp90 modulator SM258 suppresses cell proliferation, triggers apoptosis, regulates the expression of Hsp90-associated heat shock proteins, and enhances the degradation of Hsp90's client proteins preferentially in cancer cells over normal cells. Our findings support a new paradigm that AUY922 is not tumor selective, whereas SM258 is more selective and likely acts through an Hsp90-dependent mechanism.
authors.affiliation: Department of Medicine, University of New South Wales, 2052, Australia.
authors.forename: Yao
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Chemistry, University of New South Wales, Sydney, NSW, 2052, Australia.
authors.forename: Yen Chin
authors.initials: YC
authors.lastname: Koay
authors.affiliation: School of Chemistry, University of New South Wales, Sydney, NSW, 2052, Australia.
authors.forename: Shelli R
authors.identifier: 0000-0003-1058-5252
authors.initials: SR
authors.lastname: McAlpine
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D045325:HCT116 Cells; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000076249:Heat Shock Transcription Factors; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry / Q000633:toxicity*; D012333:RNA, Messenger / Q000378:metabolism; D012118:Resorcinols / Q000737:chemistry / Q000633:toxicity*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D018841:HSP90 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D007555:Isoxazoles; D012333:RNA, Messenger; D012118:Resorcinols; D014157:Transcription Factors
keywords: HCT116; SM258; anticancer agents; heat shock protein 90; luminespib