TY  - JOUR
A1  - Michaelis, Martin
A1  - Rothweiler, Florian
A1  - Barth, Susanne
A1  - Cinatl, Jindrich
A1  - Rikxoort, Marijke van
A1  - Löschmann, Nadine
A1  - Voges, Yvonne
A1  - Breitling, Rainer
A1  - Deimling, Andreas von
A1  - Rödel, Franz
A1  - Weber, Kristoffer
A1  - Fehse, Boris
A1  - Mack, Elisabeth
A1  - Stiewe, Thorsten
A1  - Doerr, Hans Wilhelm
A1  - Speidel, Daniel
A1  - Cinatl, Jindrich
T1  - 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
T2  - Cell death & disease
N2  - 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-3rNutlin10 μM, harbouring a G245C mutation) were also radiation resistant. Analysis of UKF-NB-3 and UKF-NB-3rNutlin10 μM cells by RNA interference experiments and lentiviral transduction of wild-type p53 into p53-mutated UKF-NB-3rNutlin10 μM cells revealed that the loss of p53 function contributes to the multi-drug resistance of UKF-NB-3rNutlin10 μM cells. Bioinformatics PANTHER pathway analysis based on microarray measurements of mRNA abundance indicated a substantial overlap in the signalling pathways differentially regulated between UKF-NB-3rNutlin10 μM and UKF-NB-3 and between UKF-NB-3 and its cisplatin-, doxorubicin-, or vincristine-resistant sublines. Repeated nutlin-3 adaptation of neuroblastoma cells resulted in sublines harbouring various p53 mutations with high frequency. A p53 wild-type single cell-derived UKF-NB-3 clone was adapted to nutlin-3 in independent experiments. Eight out of ten resulting sublines were p53-mutated harbouring six different p53 mutations. This indicates that nutlin-3 induces de novo p53 mutations not initially present in the original cell population. Therefore, nutlin-3-treated cancer patients should be carefully monitored for the emergence of p53-mutated, multi-drug-resistant cells.
KW  - nutlin-3
KW  - MDM2
KW  - p53
KW  - chemotherapy
KW  - chemoresistance
Y1  - 2011
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/27896
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-278967
SN  - 2041-4889
N1  - Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http:// creativecommons.org/licenses/by-nc-sa/3.0/
VL  - 2
IS  - e243
PB  - Nature Publishing Group
CY  - London [u.a.]
ER  -