Bcl-2 independence of flavopiridol-induced apoptosis. Mitochondrial depolarization in the absence of cytochrome c release

• Published in: The Journal of biological chemistry 2000-10, Vol.275 (41), p.32089
• Main Authors: Achenbach, T V, Müller, R, Slater, E P
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Bongkrekic Acid - pharmacology; Camptothecin - pharmacology; Caspase Inhibitors; Caspases - metabolism; Cytochrome c Group - metabolism; Enzyme Activation - drug effects; Enzyme Precursors - metabolism; Flavonoids - pharmacology; Gene Expression; Gene Expression Regulation, Neoplastic - drug effects; Humans; Immunohistochemistry; Ion Channels; Membrane Potentials - drug effects; Membrane Proteins - antagonists & inhibitors; Membrane Proteins - metabolism; Mitochondria - drug effects; Mitochondria - enzymology; Mitochondria - metabolism; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Oligonucleotides, Antisense - genetics; Oligonucleotides, Antisense - metabolism; Piperidines - pharmacology; Poly(ADP-ribose) Polymerases - metabolism; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Transfection; Tumor Cells, Cultured
• ISSN: 0021-9258
• DOI: 10.1074/jbc.M005267200

The new chemotherapeutic agent, flavopiridol, presently in clinical trials, has been extensively studied yet little is known about its mechanism of action. In this study we show that the induction of apoptosis by flavopiridol is largely independent of Bcl-2. This is indicated by the observation that neither overexpression nor the antisense oligonucleotide-mediated down-regulation of Bcl-2 had any effect on flavopiridol-induced cell killing. Our results suggest that flavopiridol can induce apoptosis through different pathways of caspase activation with caspase 8 playing a pivotal role. In human lung carcinoma cells, which contain high levels of endogenous Bcl-2 and lack procaspase 8, flavopiridol treatment leads to mitochondrial depolarization in the absence of cytochrome c release, followed by the activation of caspase 3 and cell death. These results clearly differ from observations made with other anti-tumor drugs and might explain, at least in part, the unusual anti-tumor properties of flavopiridol.