TY  - JOUR
A1  - Ehrhardt, Harald
A1  - Höfig, Ines
A1  - Wachter, Franziska
A1  - Obexer, Petra
A1  - Fulda, Simone
A1  - Terziyska, Nadia
A1  - Jeremias, Irmela
T1  - NOXA as critical mediator for drug combinations in polychemotherapy
T2  - Cell death & disease
N2  - During polychemotherapy, cytotoxic drugs are given in combinations to enhance their anti-tumor effectiveness. For most drug combinations, underlying signaling mechanisms responsible for positive drug-drug interactions remain elusive. Here, we prove a decisive role for the Bcl-2 family member NOXA to mediate cell death by certain drug combinations, even if drugs were combined which acted independently from NOXA, when given alone. In proof-of-principle studies, betulinic acid, doxorubicin and vincristine induced cell death in a p53- and NOXA-independent pathway involving mitochondrial pore formation, release of cytochrome c and caspase activation. In contrast, when betulinic acid was combined with either doxorubicine or vincristine, cell death signaling changed considerably; the drug combinations clearly depended on both p53 and NOXA. Similarly and of high clinical relevance, in patient-derived childhood acute leukemia samples the drug combinations, but not the single drugs depended on p53 and NOXA, as shown by RNA interference studies in patient-derived cells. Our data emphasize that NOXA represents an important target molecule for combinations of drugs that alone do not target NOXA. NOXA might have a special role in regulating apoptosis sensitivity in the complex interplay of polychemotherapy. Deciphering the differences in signaling of single drugs and drug combinations might enable designing highly effective novel polychemotherapy regimens.
KW  - NOXA
KW  - p53
KW  - betulinic acid
KW  - doxorubicin
KW  - PUMA
Y1  - 2012
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/28893
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-288933
SN  - 2041-4889
VL  - 3
IS  - e327
PB  - Nature Publishing Group
CY  - London [u.a.]
ER  -