Nutlin-3, the small-molecule inhibitor of MDM2, promotes senescence and radiosensitises laryngeal carcinoma cells harbouring wild-type p53

• Published in: British journal of cancer Vol. 103; no. 2; pp. 186 - 195
• Main Authors: Arya, A K, El-Fert, A, Devling, T, Eccles, R M, Aslam, M A, Rubbi, C P, Vlatković, N, Fenwick, J, Lloyd, B H, Sibson, D R, Jones, T M, Boyd, M T
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13-07-2010; Nature Publishing Group
• Subjects: 631/92/96; 692/699/67/1813/1352; 692/700/565/485; Animals; Apoptosis; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cancer therapies; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - radiotherapy; Cell cycle; Cell Proliferation - drug effects; Cell Survival - drug effects; Cellular Senescence - drug effects; DNA damage; Drug Resistance; Epidemiology; Genes; Genes, p53; Imidazoles - analysis; Imidazoles - pharmacology; Laryngeal cancer; Laryngeal Neoplasms - drug therapy; Laryngeal Neoplasms - genetics; Laryngeal Neoplasms - radiotherapy; Larynx; Medical research; Medical sciences; Molecular Medicine; Mutation; Oncology; Otorhinolaryngology. Stomatology; Piperazines - analysis; Piperazines - pharmacology; Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors; Radiation therapy; Radiation Tolerance - drug effects; Radiation-Sensitizing Agents - pharmacology; Senescence; Toxicity; Translational Therapeutics; Tumors; Upper respiratory tract, upper alimentary tract, paranasal sinuses, salivary glands: diseases, semeiology; United Kingdom > UK; Nutlin-3; MDM2; ionising radiation; laryngeal cancer; squamous cell carcinoma of the head and neck; p53; Laryngeal cancer; Larynx carcinoma; Senescence; Nutlin; Malignant tumor; Wild type; mdm2 Gene; Cancerology; TP53 Gene; C-Onc gene; ENT disease; Head and neck cancer; Head and neck squamous cell carcinoma; Inhibitor; Larynx disease; Protooncogene; Cancer; Tumor suppressor gene
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6605739

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.