PMID- 20588277
OWN - NLM
STAT- MEDLINE
DCOM- 20100805
LR  - 20211020
IS  - 1532-1827 (Electronic)
IS  - 0007-0920 (Print)
IS  - 0007-0920 (Linking)
VI  - 103
IP  - 2
DP  - 2010 Jul 13
TI  - Nutlin-3, the small-molecule inhibitor of MDM2, promotes senescence and 
      radiosensitises laryngeal carcinoma cells harbouring wild-type p53.
PG  - 186-95
LID - 10.1038/sj.bjc.6605739 [doi]
AB  - 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. CONCLUSION: 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.
FAU - Arya, A K
AU  - Arya AK
AD  - Division of Surgery and Oncology, School of Cancer Studies, University of 
      Liverpool, 5th Floor. UCD Building, Daulby Street, Liverpool L69 3GA, UK.
FAU - El-Fert, A
AU  - El-Fert A
FAU - Devling, T
AU  - Devling T
FAU - Eccles, R M
AU  - Eccles RM
FAU - Aslam, M A
AU  - Aslam MA
FAU - Rubbi, C P
AU  - Rubbi CP
FAU - Vlatkovic, N
AU  - Vlatkovic N
FAU - Fenwick, J
AU  - Fenwick J
FAU - Lloyd, B H
AU  - Lloyd BH
FAU - Sibson, D R
AU  - Sibson DR
FAU - Jones, T M
AU  - Jones TM
FAU - Boyd, M T
AU  - Boyd MT
LA  - eng
GR  - 8313/CRUK_/Cancer Research UK/United Kingdom
PT  - Journal Article
DEP - 20100629
PL  - England
TA  - Br J Cancer
JT  - British journal of cancer
JID - 0370635
RN  - 0 (Imidazoles)
RN  - 0 (Piperazines)
RN  - 0 (Radiation-Sensitizing Agents)
RN  - 53IA0V845C (nutlin 3)
RN  - EC 2.3.2.27 (MDM2 protein, human)
RN  - EC 2.3.2.27 (Proto-Oncogene Proteins c-mdm2)
SB  - IM
MH  - Animals
MH  - Carcinoma, Squamous Cell/*drug therapy/genetics/radiotherapy
MH  - Cell Proliferation/drug effects
MH  - Cell Survival/drug effects
MH  - Cellular Senescence/*drug effects
MH  - *Genes, p53
MH  - Imidazoles/*analysis/*pharmacology
MH  - Laryngeal Neoplasms/*drug therapy/genetics/radiotherapy
MH  - Piperazines/*analysis/*pharmacology
MH  - Proto-Oncogene Proteins c-mdm2/*antagonists & inhibitors
MH  - Radiation Tolerance/*drug effects
MH  - Radiation-Sensitizing Agents/*pharmacology
PMC - PMC2906734
EDAT- 2010/07/01 06:00
MHDA- 2010/08/06 06:00
PMCR- 2011/07/13
CRDT- 2010/07/01 06:00
PHST- 2010/07/01 06:00 [entrez]
PHST- 2010/07/01 06:00 [pubmed]
PHST- 2010/08/06 06:00 [medline]
PHST- 2011/07/13 00:00 [pmc-release]
AID - 6605739 [pii]
AID - 10.1038/sj.bjc.6605739 [doi]
PST - ppublish
SO  - Br J Cancer. 2010 Jul 13;103(2):186-95. doi: 10.1038/sj.bjc.6605739. Epub 2010 
      Jun 29.