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Induction of p53-Dependent Senescence by the MDM2 Antagonist Nutlin-3a in Mouse Cells of Fibroblast Origin

¹ Molecular Oncology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain and ² Discovery Oncology, Hoffmann-La Roche, Inc., Nutley, New Jersey

Requests for reprints: Manuel Serrano, Spanish National Cancer Research Center (CNIO), 3 Melchor Fernandez Almagro Street, Madrid E-28029, Spain. Phone: 34-91-732-8032; Fax: 34-91-732-8028; E-mail: mserrano{at}cnio.es.

Cellular senescence is emerging as an important in vivo anticancer response elicited by multiple stresses, including currently used chemotherapeutic drugs. Nutlin-3a is a recently discovered small-molecule antagonist of the p53-destabilizing protein murine double minute-2 (MDM2) that induces cell cycle arrest and apoptosis in cancer cells with functional p53. Here, we report that nutlin-3a induces cellular senescence in murine primary fibroblasts, oncogenically transformed fibroblasts, and fibrosarcoma cell lines. No evidence of drug-induced apoptosis was observed in any case. Nutlin-induced senescence was strictly dependent on the presence of functional p53 as revealed by the fact that cells lacking p53 were completely insensitive to the drug, whereas cells lacking the tumor suppressor alternative reading frame product of the CDKN2A locus underwent irreversible cell cycle arrest. Interestingly, irreversibility was achieved in neoplastic cells faster than in their corresponding parental primary cells, suggesting that nutlin-3a and oncogenic signaling cooperate in activating p53. Our current results suggest that senescence could be a major cellular outcome of cancer therapy by antagonists of the p53-MDM2 interaction, such as nutlin-3a. [Cancer Res 2007;67(15):7350–7]

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