title: The anticancer effects of chaetocin are independent of programmed cell death and hypoxia, and are associated with inhibition of endothelial cell proliferation.
abstract: BACKGROUND
  We previously reported that chaetocin has potent and selective anti-myeloma activity attributable to reactive oxygen species (ROS) induction imposed by inhibition of the redox enzyme thioredoxin reductase; we now detail its effects in solid tumours.
  
  
  METHODS
  Cellular assays, transcriptional profiling and the NCI60 screen were used to assess the effects of chaetocin in solid tumour and endothelial cells.
  
  
  RESULTS
  NCI-60 screening demonstrated chaetocin to even more potently inhibit proliferation in solid tumour than in haematological cell lines; transcriptional profiling revealed a signature consistent with induction of inflammatory response and cell death pathways. Chaetocin induced ROS, oxidative damage to cellular proteins and apoptosis, with 2-10 nM IC(50)s (24 h exposures) in all tested solid tumour cell lines. The pan-caspase inhibitor zVAD-fmk did not block chaetocin-induced cell death despite inhibiting mitochondrial membrane depolarisation and apoptosis. Further, Molt-4 rho(0) cells lacking metabolically functional mitochondria were readily killed by chaetocin; in addition chaetocin-induced cytotoxicity was unaffected by autophagy inhibitors or hypoxia and consequent HIF-1α upregulation. Moreover, chaetocin inhibited SKOV3 ovarian cancer xenografts producing less vascular tumours, and inhibited human umbilical vein endothelial cell proliferation.
  
  
  CONCLUSIONS
  Chaetocin has intriguing and wide-ranging in vitro and in vivo anticancer effects, and is an attractive candidate for further preclinical and clinical development.
authors.affiliation: Department of Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: C R
authors.initials: CR
authors.lastname: Isham
authors.forename: J D
authors.initials: JD
authors.lastname: Tibodeau
authors.forename: A R
authors.initials: AR
authors.lastname: Bossou
authors.forename: J R
authors.initials: JR
authors.lastname: Merchan
authors.forename: K C
authors.initials: KC
authors.lastname: Bible
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015687:Cell Hypoxia / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D010879:Piperazines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010879:Piperazines; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C002511:chaetocin; D040281:Vascular Endothelial Growth Factor Receptor-1