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Troglitazone: From an insulin sensit...

Chen, Kuen-Feng.

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Troglitazone: From an insulin sensitizer to a novel class of anti-cancer agent.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Troglitazone: From an insulin sensitizer to a novel class of anti-cancer agent./
Author:	Chen, Kuen-Feng.
Description:	131 p.
Notes:	Source: Dissertation Abstracts International, Volume: 66-10, Section: B, page: 5342.
Contained By:	Dissertation Abstracts International66-10B.
Subject:	Health Sciences, Pharmacy. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3193288
ISBN:	0542373521

Troglitazone: From an insulin sensitizer to a novel class of anti-cancer agent.
Chen, Kuen-Feng.

Troglitazone: From an insulin sensitizer to a novel class of anti-cancer agent. - 131 p.

Source: Dissertation Abstracts International, Volume: 66-10, Section: B, page: 5342.

Thesis (Ph.D.)--The Ohio State University, 2005.

Troglitazone (TG) holds a unique apoptosis-inducing ability, which is not found in other synthetic peroxisome proliferator-activated receptor gamma (PPARgamma) ligands like rosiglitazone or pioglitazone, and we have reported that the inhibition of Bcl-2/Bcl-xL functions is a major PPARgamma independent mechanism for apoptosis-inducing effect of troglitazone.

ISBN: 0542373521Subjects--Topical Terms:

1017737
Health Sciences, Pharmacy.

Troglitazone: From an insulin sensitizer to a novel class of anti-cancer agent.
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100 1 $a Chen, Kuen-Feng. $3 1905176
245 1 0 $a Troglitazone: From an insulin sensitizer to a novel class of anti-cancer agent.
300 $a 131 p.
500 $a Source: Dissertation Abstracts International, Volume: 66-10, Section: B, page: 5342.
500 $a Adviser: Ching-Shih Chen.
502 $a Thesis (Ph.D.)--The Ohio State University, 2005.
520 $a Troglitazone (TG) holds a unique apoptosis-inducing ability, which is not found in other synthetic peroxisome proliferator-activated receptor gamma (PPARgamma) ligands like rosiglitazone or pioglitazone, and we have reported that the inhibition of Bcl-2/Bcl-xL functions is a major PPARgamma independent mechanism for apoptosis-inducing effect of troglitazone.
520 $a In this study, we start from exploring an interesting drugs interaction between TG and celecoxib. Our data indicates 10 muM celecoxib can sensitize TG-induced apoptosis in PC-3 cells and HT-29 cells. This effect is not related to either cyclooxygenase-2 (Cox-2) activity of celecoxib or PPARgamma activity of TG. In addition, TG-88, a derivative of TG with higher Bcl-2/Bcl-xL inhibitory activity also shows the same synergy with celecoxib, suggesting the Bcl-2/Bcl-xL functions play an important role in this interaction.
520 $a Our previous study identified Bcl-xL provides a survival mechanism of PC-3 cells suffered from the inhibition of PI3K/AKT signaling pathway We hypothesize the combination of PDKI/AKT inhibition and Bcl-xL inhibition can exhibit maximal apoptosis-inducing effect in PC-3 cells. We employ OSU-03012, a PDK1/AKT inhibitor derived from celecoxib, and TG-88 to examine this premise. Our data shows OSU-03012 at 5 muM is able to potentiate 5 muM TG-88-induced apoptosis in PC-3 cells. In addition, animal studies of PC-3 xenograft model demonstrate the combination of TG-88 at 200 mg/kg/day and either OSU-03012 at 100 mg/kg/day or 200mg/kg/day can achieve maximal anti-tumor activity after 6 weeks of treatment. Furthermore, we studied another anti-cancer effect of TG, which is to sensitize the effect of TRAIL (TNF-related apoptosis inducing ligand) in cancer cells. Our data shows TG can sensitize TRAIL induced cell death in HT-29 and LNCaP cells via a PPARgamma independent mechanism. Evidence from TG-88 and LNCaP cells with high expression of Bcl-xL indicates the inhibition of Bcl-2/Bcl-xL play a critical role in this TRAIL sensitizing effect of TG. Moreover, we sensitize HT-29 to TRAIL-induced cell death by reducing the expression of Bcl-xL in HT-29 through the supplement of small interference RNA, supporting the inhibition of Bcl-xL is able to enhance the effect of TRAIL.
590 $a School code: 0168.
650 4 $a Health Sciences, Pharmacy. $3 1017737
650 4 $a Health Sciences, Oncology. $3 1018566
650 4 $a Biology, Cell. $3 1017686
650 4 $a Health Sciences, Pharmacology. $3 1017717
690 $a 0572
690 $a 0992
690 $a 0379
690 $a 0419
710 2 0 $a The Ohio State University. $3 718944
773 0 $t Dissertation Abstracts International $g 66-10B.
790 1 0 $a Chen, Ching-Shih, $e advisor
790 $a 0168
791 $a Ph.D.
792 $a 2005
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3193288