NOXA as critical mediator for drug combinations in polychemotherapy.
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.
Helmholtz Center Munich - German Research Center for Environmental Health, Marchioninistrasse 25, 81377 Munich, Germany.
H
H
Ehrhardt
I
I
Höfig
F
F
Wachter
P
P
Obexer
S
S
Fulda
N
N
Terziyska
I
I
Jeremias
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002648:Child; D004317:Doxorubicin / Q000494:pharmacology; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D053978:Pentacyclic Triterpenes; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D014315:Triterpenes / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D014750:Vincristine / Q000494:pharmacology; D000094062:Betulinic Acid
D000970:Antineoplastic Agents; D004338:Drug Combinations; C498702:PMAIP1 protein, human; D053978:Pentacyclic Triterpenes; D019253:Proto-Oncogene Proteins c-bcl-2; D014315:Triterpenes; D016159:Tumor Suppressor Protein p53; D014750:Vincristine; D004317:Doxorubicin; D000094062:Betulinic Acid