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, JONES, T. M, BOYD, M. T, DEVLING, T, ECCLES, R. M, ASLAM, M. A, RUBBI, C. P, VLATKOVIC, N, FENWICK, J, LLOYD, B. H, SIBSON, D. R
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 13.07.2010
• Subjects: Animals; Apoptosis; Biological and medical sciences; 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; Genes; Genes, p53; Imidazoles - analysis; Imidazoles - pharmacology; Laryngeal cancer; Laryngeal Neoplasms - drug therapy; Laryngeal Neoplasms - genetics; Laryngeal Neoplasms - radiotherapy; Larynx; Medical research; Medical sciences; Mutation; 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; Laryngeal cancer; Larynx carcinoma; Senescence; Nutlin; Malignant tumor; Wild type; squamous cell carcinoma of the head and neck; mdm2 Gene; p53; ionising radiation; Cancerology; TP53 Gene; C-Onc gene; MDM2; 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

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. 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. 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. 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.