Nongenotoxic p53 activation protects cells against S-phase-specific chemotherapy.
Mutations in the tumor suppressor gene TP53 represent the most frequent genetic difference between tumor cells and normal cells. Here, we have attempted to turn this difference into an advantage for normal cells during therapy. Using the Mdm2 antagonist nutlin-3, we first activated p53 in U2OS and HCT116 cells to induce cell cycle arrest. These arrested cells were found to be resistant to subsequent transient treatment with the nucleoside analogue gemcitabine, as revealed by clonogenic assays following drug removal. In contrast, isogenic cells lacking functional p53 continued to enter S phase regardless of nutlin-3 pretreatment and remained highly susceptible to gemcitabine-mediated cytotoxicity. The sequential treatment with nutlin-3 alone, followed by transient exposure to nutlin-3 plus gemcitabine, efficiently compromised the clonogenicity of tumor cells with deletions or mutations of p53 but largely spared the proliferation of nontransformed human keratinocytes. Nutlin-3 pretreatment also conferred protection of p53-proficient cells against cytosine arabinoside but not against doxorubicin or cisplatin. We propose that the cell cycle arrest function of p53 can be used to convert p53 from a killer to a protector of cells, with the potential to reduce unwanted side effects of chemotherapy.
Kranz
Dominique
D
Medical Biotechnology Center, Institute for Medical Biology, University of Southern Denmark, Odense, Denmark.
Dobbelstein
Matthias
M
D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D019610:Cytoprotection; D004273:DNA, Neoplasm / Q000032:analysis; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D005434:Flow Cytometry; D016158:Genes, p53 / Q000502:physiology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D015603:Keratinocytes / Q000187:drug effects; D009154:Mutation; D010879:Piperazines / Q000494:pharmacology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D016196:S Phase / Q000187:drug effects*; D000093542:Gemcitabine
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D007093:Imidazoles; D010879:Piperazines; D003841:Deoxycytidine; C482205:nutlin 3; D004317:Doxorubicin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D002945:Cisplatin; D000093542:Gemcitabine