Adaptation of cancer cells from different entities to the MDM2 inhibitor nutlin-3 results in the emergence of p53-mutated multi-drug-resistant cancer cells.

ABSTRACT: Six p53 wild-type cancer cell lines from infrequently p53-mutated entities (neuroblastoma, rhabdomyosarcoma, and melanoma) were continuously exposed to increasing concentrations of the murine double minute 2 inhibitor nutlin-3, resulting in the emergence of nutlin-3-resistant, p53-mutated sublines displaying a multi-drug resistance phenotype. Only 2 out of 28 sublines adapted to various cytotoxic drugs harboured p53 mutations. Nutlin-3-adapted UKF-NB-3 cells (UKF-NB-3(r)Nutlin(10 μM), harbouring a G245C mutation) were also radiation resistant. Analysis of UKF-NB-3 and UKF-NB-3(r)Nutlin(10 μM) cells by RNA interference experiments and lentiviral transduction of wild-type p53 into p53-mutated UKF-NB-3(r)Nutlin(10 μM) cells revealed that the loss of p53 function contributes to the multi-drug

SUBMITTER: Michaelis M 

PROVIDER: S-EPMC3252738 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature