A crucial role of caspase 3 and caspase 8 in paclitaxel-induced apoptosis.
The anticancer drug paclitaxel is well known as an inhibitor of microtubule depolymerization, resulting in mitosis arrest. We investigated the mechanism underlying antitumor effects of paclitaxel on the lung adenocarcinoma cell line LC-2-AD. Less than 10 microg/ml paclitaxel induced mitosis arrest upon LC-2-AD, followed by apoptosis, but more than 30 microg/ml paclitaxel induced apoptosis without mitosis arrest. LC-2-AD with less than 1 microg/ml paclitaxel showed a loss of mitochondrial transmembrane potential (deltapsim), which correlated with antitumor effects. However, LC-2-AD with more than 10 microg/ml paclitaxel showed slight changes in the loss of deltapsim in spite of its ability to induce apoptosis significantly. The cleavage of caspase 3, caspase 8, and DFF45/ICAD was also observed in paclitaxel-induced apoptosis, and the inhibitor of caspase 3 and caspase 8 inhibited both antitumor effects and apoptosis induced by paclitaxel. These results suggest that activation of caspase 3 and caspase 8 plays a crucial role in paclitaxel-induced apoptosis under any concentrations of paclitaxel.
Oyaizu
H
H
First Department of Pathology, Kansai Medical University, Moriguchi, Osaka, Japan.
Adachi
Y
Y
Taketani
S
S
Tokunaga
R
R
Fukuhara
S
S
Ikehara
S
S
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D004789:Enzyme Activation; D005470:Fluorometry; D006801:Humans; D015151:Immunoblotting; D017239:Paclitaxel / Q000494:pharmacology*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D019014:fas Receptor; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D017239:Paclitaxel