Necessity of interleukin-1beta converting enzyme cascade in taxotere-initiated death signaling.
Taxotere is a new type chemotherapeutic agent which targets tubulin. In the present study, we investigated the molecular machinery of taxotere-initiated death signaling. Taxotere induced cell death in mouse fibroblast L929 cells. Cell morphological analysis revealed that this effect showed characteristics of apoptotic and necrotic cell death. To further examine taxotere-induced cell death, we investigated the direct involvement of caspase. When cells were pretreated with the synthesized tetrapeptide inhibitor of caspase, YVAD-CHO (Ac-Tyr-Val-Ala-Asp-aldehyde: inhibitor of interleukin-1beta converting enzyme (ICE) subfamily) or DEVD-CHO (Ac-Asp-Glu-Val-Asp-aldehyde: inhibitor of CPP32 subfamily), taxotere-induced cell death was prevented. In addition, time course experiments demonstrated that activation of the ICE subfamily preceded activation of the CPP32 subfamily in taxotere-initiated death signaling, suggesting the direct involvement of the ICE cascade in taxotere-initiated death signaling. On the basis of these results, we suggest that taxotere causes the initiation of ICE cascade in its death signaling pathway and that the down-stream site of taxotere-initiated death signaling is the same as that of other chemotherapeutic agents.
Suzuki
A
A
Drug Safety Research Laboratory, Daiichi Pharmaceutical Co. Ltd., Tokyo R&D Center 16-13, Japan. LEB00373@niftyserve.or.jp
Kawabata
T
T
Kato
M
M
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000502:physiology*; D020170:Caspase 1; D004396:Coloring Agents; D003546:Cysteine Endopeptidases / Q000502:physiology*; D000077143:Docetaxel; D007739:L Cells; D051379:Mice; D009336:Necrosis; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000494:pharmacology; D043823:Taxoids
D000972:Antineoplastic Agents, Phytogenic; D004396:Coloring Agents; D043823:Taxoids; D000077143:Docetaxel; D003546:Cysteine Endopeptidases; D020170:Caspase 1; D017239:Paclitaxel