bongkrekic-acid and alvocidib

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.

Topics: Antineoplastic Agents; Apoptosis; Bongkrekic Acid; Camptothecin; Caspase Inhibitors; Caspases; Cytochrome c Group; Enzyme Activation; Enzyme Precursors; Flavonoids; Gene Expression; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Ion Channels; Membrane Potentials; Membrane Proteins; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Oligonucleotides, Antisense; Piperidines; Poly(ADP-ribose) Polymerases; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-bcl-2; Transfection; Tumor Cells, Cultured