title: The pan-Bcl-2 inhibitor (-)-gossypol triggers autophagic cell death in malignant glioma.
abstract: Antiapoptotic Bcl-2 family members suppress both apoptosis and autophagy and are of major importance for therapy resistance of malignant gliomas. To target these molecules, we used BH3 mimetics and analyzed the molecular mechanisms of cell death induced thereby. Glioma cells displayed only limited sensitivity to single-agent treatment with the BH3 mimetics HA14-1, BH3I-2', and ABT-737, whereas the pan-Bcl-2 inhibitor (-)-gossypol efficiently induced cell death. Furthermore, (-)-gossypol potentiated cell death induced by temozolomide (TMZ) in MGMT (O(6)-methylguanine-DNA methyltransferase)-negative U343 cells and, to a lesser extent, in MGMT-expressing U87 cells. (-)-Gossypol triggered translocation of light chain 3 to autophagosomes and lysosomes and cytochrome c release, but cell death occurred in the absence of lysosomal damage and effector caspase activation. Lentiviral knockdown of Beclin1 and Atg5 in U87, U343, and MZ-54 cells strongly diminished the extent of cell death induced by (-)-gossypol and combined treatment with TMZ, indicating that autophagy contributed to this type of cell death. In contrast, stable knockdown of the endogenous autophagy inhibitor mammalian target of rapamycin increased autophagic cell death. Our data suggest that pan-Bcl-2 inhibitors are promising drugs that induce caspase-independent, autophagic cell death in apoptosis-resistant malignant glioma cells and augment the action of TMZ. Furthermore, they indicate that efficient killing of glioma cells requires neutralization of Mcl-1.
authors.affiliation: Experimental Neurosurgery, Goethe-University Hospital, Frankfurt, Germany.
authors.forename: Valerie
authors.initials: V
authors.lastname: Voss
authors.forename: Christian
authors.initials: C
authors.lastname: Senft
authors.forename: Verena
authors.initials: V
authors.lastname: Lang
authors.forename: Michael W
authors.initials: MW
authors.lastname: Ronellenfitsch
authors.forename: Joachim P
authors.initials: JP
authors.lastname: Steinbach
authors.forename: Volker
authors.initials: V
authors.lastname: Seifert
authors.forename: Donat
authors.initials: D
authors.lastname: Kögel
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D015254:DNA Modification Methylases / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000378:metabolism; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D004789:Enzyme Activation; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006072:Gossypol / Q000494:pharmacology*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D000077204:Temozolomide; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D020169:Caspases; D045643:DNA Repair Enzymes; D006072:Gossypol; D000077204:Temozolomide