Mechanisms of Taxotere-induced apoptosis in or a squamous cell carcinoma.
| Project/Area Number |
16390577
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Surgical dentistry
|
|---|
| Research Institution | TOHOKU UNIVERSITY |
|---|
Principal Investigator |
RIKIISHI Hidemi Tohoku University, Graduate School of Dentistry, Associate Professor, 大学院歯学研究科, 助教授 (70091767)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
ECHIGO Seishi Tohoku University, Graduate School of Dentistry, Professor, 大学院歯学研究科, 教授 (70005114)
HASHIMOTO Wataru Tohoku University, Hospital, Assistant, 病院・助手 (30323033)
|
|---|
| Project Period (FY) |
2004 – 2006
|
| Project Status |
Completed (Fiscal Year 2006)
|
| Budget Amount *help |
¥10,400,000 (Direct Cost: ¥10,400,000)
Fiscal Year 2006: ¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2005: ¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2004: ¥4,000,000 (Direct Cost: ¥4,000,000)
|
|---|
| Keywords | Taxotere / Selenium compounds / Cisplatin / Apoptosis / Caspase / Mitochondria / Cytochrome C / Reactive oxygen species / 併用療法 / epigenetics / グルタチオン / 増強剤 / 膜電位 |
|---|
| Research Abstract |
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
|
Report
(4 results)
Research Products
(12 results)
