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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)
Verlagsversion Volltext DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter 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
ISSN (print) / ISBN 2041-4889
e-ISSN 2041-4889
Zeitschrift Cell Death & Disease
Quellenangaben Band: 3, Heft: 6, Seiten: e327 Artikelnummer: e327 Supplement: ,
Verlag Nature Publishing Group
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Gene Vector (AGV)