Mechanisms of Taxotere-induced apoptosis in or a squamous cell carcinoma.

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Apoptosis induced by Taxotere that interferes with microtubule polymerization dynamics and is used clinically to treat advanced cancers, has not been fully defined in squamous cell carcinoma. In this study, apoptotic events involved in Taxotere treatment were investigated. When the human oral squamous cell carcinoma cell line HSC-3 was exposed to Taxotere for 72 h, a dose-dependent effect was observed in apoptosis using the TUNEL method. We observed activation of caspase cascade including activities like caspase-3,-8,and-9. And the pan-caspase inhibitor z-VAD-fmk prevented apoptosis induced by Taxotere (0.1 μM), showing participation of caspases in this process. Since an antagonistic CD95-antibody (ZB4) exerted no effect on Taxotere-induced apoptosis, CD95/CD95L interaction was not involved in this pathway. The caspase-8-like activity was inhibited not only by IETD-fmk (caspase-8) but also by DEVD-fmk (caspase-3). The results indicate that the caspase-8-like activation occurred downstream of DEVDase. Taxotere promoted the formation of reactive oxygen species (ROS) in mitochondria, and preincubation of cells with anti-oxidants such as N-acetyl cysteine and pyrrolidine dithiocarbamate, protected against apoptosis mediated by Taxotere. Furthermore, treatment with Taxotere elicited reduction of mitochondrial membrane potential, and release of cytochrome c to cytosol, after 48 h of treatment. We observed binding activity to NF-κB consensus site and interference with the mitochondrial function via NF-κB after Taxotere treatment. Preventing pro-apoptotic property of NF-κB inhibited Taxotere-induced apoptosis. Thus, these results suggest that, following the activation of NF-κB by Taxotere, apoptosis is elicited through a mitochondria-dependent pathway