title: Activation of the stress proteome as a mechanism for small molecule therapeutics.
abstract: Various small molecule pharmacologic agents with different known functions produce similar outcomes in diverse Mendelian and complex disorders, suggesting that they may induce common cellular effects. These molecules include histone deacetylase inhibitors, 4-phenylbutyrate (4PBA) and trichostatin A, and two small molecules without direct histone deacetylase inhibitor activity, hydroxyurea (HU) and sulforaphane. In some cases, the therapeutic effects of histone deacetylase inhibitors have been attributed to an increase in expression of genes related to the disease-causing gene. However, here we show that the pharmacological induction of mitochondrial biogenesis was necessary for the potentially therapeutic effects of 4PBA or HU in two distinct disease models, X-linked adrenoleukodystrophy and sickle cell disease. We hypothesized that a common cellular response to these four molecules is induction of mitochondrial biogenesis and peroxisome proliferation and activation of the stress proteome, or adaptive cell survival response. Treatment of human fibroblasts with these four agents induced mitochondrial and peroxisomal biogenesis as monitored by flow cytometry, immunofluorescence and/or western analyses. In treated normal human fibroblasts, all four agents induced the adaptive cell survival response: heat shock, unfolded protein, autophagic and antioxidant responses and the c-jun N-terminal kinase pathway, at the transcriptional and translational levels. Thus, activation of the evolutionarily conserved stress proteome and mitochondrial biogenesis may be a common cellular response to such small molecule therapy and a common basis of therapeutic action in various diseases. Modulation of this novel therapeutic target could broaden the range of treatable diseases without directly targeting the causative genetic abnormalities.
authors: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
authors: Rebecca Deering
authors: RD
authors: Brose
authors: Gloria
authors: G
authors: Shin
authors: Martina C
authors: MC
authors: McGuinness
authors: Tonya
authors: T
authors: Schneidereith
authors: Shirley
authors: S
authors: Purvis
authors: Gao X
authors: GX
authors: Dong
authors: Jeffrey
authors: J
authors: Keefer
authors: Forrest
authors: F
authors: Spencer
authors: Kirby D
authors: KD
authors: Smith
mesh_terms: D000326:Adrenoleukodystrophy / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D002460:Cell Line; D004358:Drug Therapy; D006801:Humans; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D006918:Hydroxyurea / Q000627:therapeutic use*; D017879:Isothiocyanates; D063269:Mitochondrial Turnover / Q000187:drug effects; D010654:Phenylbutyrates / Q000627:therapeutic use*; D020543:Proteome / Q000235:genetics / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000627:therapeutic use; D013454:Sulfoxides; D013861:Thiocyanates / Q000627:therapeutic use*
chemical_list: D006877:Hydroxamic Acids; D017879:Isothiocyanates; D010654:Phenylbutyrates; D020543:Proteome; D054852:Small Molecule Libraries; D013454:Sulfoxides; D013861:Thiocyanates; C012589:trichostatin A; C075773:4-phenylbutyric acid; C016766:sulforaphane; D006918:Hydroxyurea