title: Necroptosis is a novel mechanism of radiation-induced cell death in anaplastic thyroid and adrenocortical cancers.
abstract: BACKGROUND
  Necroptosis is a recently described mechanism of programmed cellular death. We hypothesize that necroptosis plays an important role in radiation-induced cell death in endocrine cancers.
  
  
  METHODS
  Thyroid and adrenocortical carcinoma cell lines were exposed to increasing doses of radiation in the presence of necroptosis inhibitor Nec-1 and/or apoptosis-inhibitor zVAD. H295R cells deficient in receptor interacting protein 1 (RIP1), an essential kinase for necroptosis, were used as controls. Survival curves were generated at increasing doses of radiation.
  
  
  RESULTS
  Nec-1 and zVAD increased cellular survival with increasing doses of radiotherapy in 8505c, TPC-1, and SW13. Both inhibitors used together had an additive effect. At 6 Gy, 8505c, TPC-1, and SW13 cell survival was significantly increased compared to controls by 40%, 33%, and 31% with Nec-1 treatment, by 53%, 47%, and 44% with zVAD treatment, and by 80%, 70%, and 65% with both compounds, respectively (P < .05). H295R showed no change in survival with Nec-1 treatment. The radiobiologic parameter quasithreshold dose was significantly increased in 8505c, TPC-1, and SW13 cells when both Nec-1 and zVAD were used in combination to inhibit necroptosis and apoptosis together, revealing resistance to standard doses of fractionated therapeutic radiation.
  
  
  CONCLUSIONS
  Necroptosis contributes to radiation-induced cell death. Future studies should investigate ways to promote the activation of necroptosis to improve radiosensitivity.
authors.affiliation: Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Nehs
authors.forename: Chi-Iou
authors.initials: CI
authors.lastname: Lin
authors.forename: David E
authors.initials: DE
authors.lastname: Kozono
authors.forename: Edward E
authors.initials: EE
authors.lastname: Whang
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Cho
authors.forename: Kaya
authors.initials: K
authors.lastname: Zhu
authors.forename: Jacob
authors.initials: J
authors.lastname: Moalem
authors.forename: Francis D
authors.initials: FD
authors.lastname: Moore
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Ruan
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000378:metabolism / Q000503:physiopathology / Q000532:radiotherapy*; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002277:Carcinoma; D002291:Carcinoma, Papillary; D016923:Cell Death / Q000187:drug effects / Q000528:radiation effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000378:metabolism; D000077273:Thyroid Cancer, Papillary; D065646:Thyroid Carcinoma, Anaplastic; D013964:Thyroid Neoplasms / Q000378:metabolism / Q000503:physiopathology / Q000532:radiotherapy*
chemical_list: C119724:AGFG1 protein, human; D007093:Imidazoles; D007211:Indoles; D028861:Nuclear Pore Complex Proteins; D009842:Oligopeptides; D016601:RNA-Binding Proteins; C517629:benzyloxycarbonyl-valyl-alanyl-aspartic acid; C507699:necrostatin-1