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  • Original Paper
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The absence of p53 is critical for the induction of apoptosis by 5-aza-2′-deoxycytidine

Abstract

The absence of functional p53 has complex consequences on the cellular responses to cytotoxic drugs. Here, we have examined the role of p53 in the response to 5-aza-2′-deoxycytidine (5-aza-dC or decitabine). Primary mouse embryonic fibroblasts deficient for p53 undergo apoptosis after treatment with 5-aza-dC. When compared with other demethylating drugs or chemotherapeutic treatments, 5-aza-dC showed the highest selectivity ratio for triggering apoptosis in p53-deficient cells relative to wild-type cells. Moreover, the apoptotic efficacy of 5-aza-dC is proprietary of p53-deficient cells, not being observed in cells lacking other cell-cycle regulators, such as p19ARF, p16INK4a, p21CIP1/WAF1, E2F-1, or E2F-2. Interestingly, treatment with 5-aza-dC results in the same degree of global genomic hypomethylation in wild-type and p53-null cells. However, wild-type cells activate p53 and arrest at G2/M, whereas p53-null cells accumulate severe chromosomal aberrations and undergo apoptosis. Significantly, the impact of p53-deficiency on the response to 5-aza-dC is not exclusive of primary non-neoplastic cells, but it is also present in neoplastically transformed cells. Finally, treatment of mice bearing genetically defined tumors with nontoxic doses of 5-aza-dC results in therapeutical responses only on tumors lacking p53, but not on tumors lacking p19ARF. Together, our results put forward the hypothesis that the absence of p53 may determine a higher chemotherapeutic index for 5-aza-dC.

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Acknowledgements

MN was supported by a fellowship from the Department of Immunology and Oncology (DIO), Spanish National Center of Biotechnology. Research at MS laboratory was funded by grants from the European Union (QLRT-2000-00616), the Spanish Ministry of Health (01/0062-02), and the Spanish Ministry of Science and Technology (SAF2002-03402). The DIO was founded and is supported by a consortium between the Spanish Council for Scientific Research (CSIC) and Pharmacia Corporation. We want to thank Lucio Gómez for helping us in the manipulation of mice, and Manuel González for his advise on retroviral infections.

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Correspondence to Manuel Serrano.

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Nieto, M., Samper, E., Fraga, M. et al. The absence of p53 is critical for the induction of apoptosis by 5-aza-2′-deoxycytidine. Oncogene 23, 735–743 (2004). https://doi.org/10.1038/sj.onc.1207175

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