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

Molecular Oncology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
Cancer Research (Impact Factor: 9.33). 09/2007; 67(15):7350-7. DOI: 10.1158/0008-5472.CAN-07-0200
Source: PubMed


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.

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    • "A number of TP53-MDM2 inhibitors are currently under investigation as therapeutic agents in a variety of clinical trials across multiple tumor types. Mechanistically, only tumors with wild-type (WT) TP53 can potentially be sensitive to TP53-MDM2 inhibitors as confirmed in part by sensitivity of WT MEFs cells and by the loss of sensitivity in TP53 knockout MEFs (Efeyan et al., 2007). Therefore, clinical trials of TP53-MDM2 inhibitors only include patients with WT TP53 tumors. "
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    ABSTRACT: A number of TP53-MDM2 inhibitors are currently under investigation as therapeutic agents in a variety of clinical trials in patients with TP53 wild type tumors. Not all wild type TP53 tumors are sensitive to such inhibitors. In an attempt to improve selection of patients with TP53 wild type tumors, an mRNA expression signature based on 13 TP53 transcriptional target genes was recently developed (Jeay et al. 2015). Careful reanalysis of TP53 status in the study validation data set of cancer cell lines considered to be TP53 wild type detected TP53 inactivating alterations in 23% of cell lines. The subsequent reanalysis of the remaining TP53 wild type cell lines clearly demonstrated that unfortunately the 13-gene signature cannot predict response to TP53-MDM2 inhibitor in TP53 wild type tumors.
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    • "Another interesting discovery is that p53-triggered senescence selectively affects tumor cells, leaving normal tissue totally unchanged (86). Novel p53-targeting compounds developed to date include Ellipticine and PRIMA-1, which restore wild-type activity to p53 mutants, and nutlins, which inhibit the binding of p53 to MDM2 (87-89). "
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    ABSTRACT: Cellular senescence is a physiological process of irreversible cell-cycle arrest that contributes to various physiological and pathological processes of aging. Whereas replicative senescence is associated with telomere attrition after repeated cell division, stress-induced premature senescence occurs in response to aberrant oncogenic signaling, oxidative stress, and DNA damage which is independent of telomere dysfunction. Recent evidence indicates that cellular senescence provides a barrier to tumorigenesis and is a determinant of the outcome of cancer treatment. However, the senescence-associated secretory phenotype, which contributes to multiple facets of senescent cancer cells, may influence both cancer-inhibitory and cancer-promoting mechanisms of neighboring cells. Conventional treatments, such as chemo- and radiotherapies, preferentially induce premature senescence instead of apoptosis in the appropriate cellular context. In addition, treatment-induced premature senescence could compensate for resistance to apoptosis via alternative signaling pathways. Therefore, we believe that an intensive effort to understand cancer cell senescence could facilitate the development of novel therapeutic strategies for improving the efficacy of anticancer therapies. This review summarizes the current understanding of molecular mechanisms, functions, and clinical applications of cellular senescence for anticancer therapy.
    Full-text · Article · Feb 2014 · BMB reports
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    • "Moreover, they confirmed that Nutlin-3a requires p53 and p21 expression to work as an anti- PH drug showing that Nutlin-3a exerts no effects on hypoxia-exposed p53 −/− and p21 −/− mice. Intriguingly, the paper also shows that Nutlin-3a treatment of cultured human PASMCs results in cell growth arrest but not apoptosis, which is consistent with other reports using fibroblasts from mice and humans (Efeyan et al., 2007; Kumamoto et al., 2008). Therefore, it appears that Nutlin-3a has a totally different mechanism of action from currently available drugs and that it is not directly associated with relaxation of smooth muscle and vasodilation of the pulmonary arteries, which lessens the concern about the side effects related to vasodilation. "

    Full-text · Article · Jul 2013 · Frontiers in Pharmacology
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