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

The new chemotherapeutic agent, flavopiridol, presently in clinical trials, has been extensively studied yet little is known about its mechanism of ac tion. 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-reg ulation of Bcl-2 had any effect on flavopiridol-induced cell killing. Our r esults suggest that flavopiridol can induce apoptosis through different pat hways of caspase activation with caspase 8 playing a pivotal role. In human lung carcinoma cells, which contain high levels of endogenous Bcl-2 and la ck procaspase 8, flavopiridol treatment leads to mitochondrial depolarizati on in the absence of cytochrome c release, followed by the activation of ca spase 3 and cell death. These results clearly differ from observations made with other anti-tumor drugs and might explain, at least in part, the unusu al anti-tumor properties of flavopirido.