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Ehrhardt, H. ; Höfig, I. ; Wachter, F. ; Obexer, P.* ; Fulda, S.* ; Terziyska, N. ; Jeremias, I.

NOXA as critical mediator for drug combinations in polychemotherapy.

Cell Death Dis. 3, e327:e327 (2012)
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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. Cell Death and Disease (2012) 3, e327; doi:10.1038/cddis.2012.53; published online 21 June 2012
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Publication type Article: Journal article
Document type Scientific Article
Keywords Noxa ; P53 ; Betulinic Acid ; Doxorubicin ; Puma; ACUTE LYMPHOBLASTIC-LEUKEMIA; ACID-INDUCED APOPTOSIS; BETULINIC ACID; TUMOR-CELLS; BH3-ONLY PROTEINS; ANTICANCER DRUGS; MELANOMA-CELLS; JURKAT CELLS; BCL-2 FAMILY; P53
Language english
Publication Year 2012
HGF-reported in Year 2012
ISSN (print) / ISBN 2041-4889
e-ISSN 2041-4889
Journal Cell Death & Disease
Quellenangaben Volume: 3, Issue: 6, Pages: e327 Article Number: e327 Supplement: ,
Publisher Nature Publishing Group
Reviewing status Peer reviewed
Institute(s) Research Unit Gene Vector (AGV)
PSP Element(s) G-550300-001
PubMed ID 22555882
DOI 10.1038/cddis.2012.53
WOS ID WOS:000305889400010
Scopus ID 84863450256
Erfassungsdatum 2012-07-26
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