The absence of p53 is critical for the induction of apoptosis by 5-aza-2'-deoxycytidine.
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, p21(CIP1/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.
Nieto
María
M
Department of Immunology and Oncology, Spanish National Center of Biotechnology (CNB), Madrid, Spain.
Samper
Enrique
E
Fraga
Mario F
MF
González de Buitrago
Gonzalo
G
Esteller
Manel
M
Serrano
Manuel
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000077209:Decitabine; D016193:G1 Phase / Q000187:drug effects; D051379:Mice; D008938:Mitosis / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D016159:Tumor Suppressor Protein p53; D000077209:Decitabine; D001374:Azacitidine