title: Nutlin-3, the small-molecule inhibitor of MDM2, promotes senescence and radiosensitises laryngeal carcinoma cells harbouring wild-type p53.
abstract: BACKGROUND
  Primary radiotherapy (RT) is a mainstay of treatment for laryngeal squamous cell carcinoma (LSCC). Although the cure rates for early (T1) vocal cord tumours are high, RT proves ineffective in up to a third of T3 carcinomas. Moreover, RT is associated with debilitating early- and late-treatment-related toxicity, thus finding means to de-escalate therapy, while retaining/augmenting therapeutic effectiveness, is highly desirable. p53 is a key mediator of radiation responses; we therefore investigated whether Nutlin-3, a small-molecule inhibitor of MDM2 (mouse double minute 2; an essential negative regulator of p53), might radiosensitise LSCC cells.
  
  
  METHODS
  We performed clonogenic assays to measure radiosensitivity in a panel of LSCC cell lines (for which we determined p53 mutational status) in the presence and absence of Nutlin-3.
  
  
  RESULTS
  LSCC cells harbouring wild-type p53 were significantly radiosensitised by Nutlin-3 (P<0.0001; log-rank scale), and displayed increased cell cycle arrest and significantly increased senescence (P<0.001) in the absence of increased apoptosis; thus, our data suggest that senescence may mediate this increased radiosensitivity.
  
  
  CONCLUSIONS
  This is the first study showing Nutlin-3 as an effective radiosensitiser in LSCC cells that retain wild-type p53. The clinical application of Nutlin-3 might improve local recurrence rates or allow treatment de-escalation in these patients.
authors.affiliation: Division of Surgery and Oncology, School of Cancer Studies, University of Liverpool, 5th Floor. UCD Building, Daulby Street, Liverpool L69 3GA, UK.
authors.forename: A K
authors.initials: AK
authors.lastname: Arya
authors.forename: A
authors.initials: A
authors.lastname: El-Fert
authors.forename: T
authors.initials: T
authors.lastname: Devling
authors.forename: R M
authors.initials: RM
authors.lastname: Eccles
authors.forename: M A
authors.initials: MA
authors.lastname: Aslam
authors.forename: C P
authors.initials: CP
authors.lastname: Rubbi
authors.forename: N
authors.initials: N
authors.lastname: Vlatković
authors.forename: J
authors.initials: J
authors.lastname: Fenwick
authors.forename: B H
authors.initials: BH
authors.lastname: Lloyd
authors.forename: D R
authors.initials: DR
authors.lastname: Sibson
authors.forename: T M
authors.initials: TM
authors.lastname: Jones
authors.forename: M T
authors.initials: MT
authors.lastname: Boyd
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000532:radiotherapy; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D016158:Genes, p53; D007093:Imidazoles / Q000032:analysis* / Q000494:pharmacology*; D007822:Laryngeal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000532:radiotherapy; D010879:Piperazines / Q000032:analysis* / Q000494:pharmacology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*
chemical_list: D007093:Imidazoles; D010879:Piperazines; D011838:Radiation-Sensitizing Agents; C482205:nutlin 3; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2