title: HSP27 knockdown produces synergistic induction of apoptosis by HSP90 and kinase inhibitors in glioblastoma multiforme.
abstract: OBJECTIVE
  The heat-shock proteins HSP27 and HSP90 perpetuate the malignant nature of glioblastoma multiforme (GBM) and offer promise as targets for novel cancer therapeutics. The present study sought to define synergistic antitumor benefits of concurrent HSP27-knockdown and the HSP90 inhibitor, 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) or, comparatively, the non-selective kinase inhibitor, staurosporine, in GBM cells.
  
  
  METHODS
  Dose-response relations were determined for 17-AAG and staurosporine in three GBM cell lines. HSP27-targeted siRNA was administered alone or in combination with subtherapeutic concentrations of each drug and cells were evaluated for viability, proliferation and apoptosis.
  
  
  RESULTS
  Adjuvant HSP27 knockdown with 17-AAG or staurosporine produced marked and synergistic decrease in GBM cell viability and proliferation, with robust elevation of apoptotic fractions and caspase-3 activation.
  
  
  CONCLUSIONS
  HSP27 knockdown confers potent chemosensitization of GBM cells. These novel data support the development of HSP-targeting strategies and, specifically, anti-HSP27 agents for the treatment of GBM.
authors.affiliation: Department of Clinical Neurological Sciences, University of Western Ontario, London, ON, Canada.
authors.forename: Louiza
authors.initials: L
authors.lastname: Belkacemi
authors.affiliation: Department of Clinical Neurological Sciences, University of Western Ontario, London, ON, Canada mhebb@uwo.ca.
authors.forename: Matthew O
authors.initials: MO
authors.lastname: Hebb
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics*; D016227:Benzoquinones / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism*; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D034622:RNA Interference
chemical_list: D016227:Benzoquinones; D055551:HSP27 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D047428:Protein Kinase Inhibitors; C112765:tanespimycin; D053148:Caspase 3
keywords: Cancer; HSP27; gene therapy; glioblastoma; molecular chaperones