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

Chen, Kuen-Feng
http://rave.ohiolink.edu/etdc/view?acc_num=osu1128057928

Abstract Details

2005, Doctor of Philosophy, Ohio State University, Pharmacy.
Troglitazone (TG) hold a unique apoptosis-inducing ability, which is not found in other synthetic peroxisome proliferator-activated receptor gamma ligands like rosiglitazone or pioglitaozne, and we have reported that the inhibition of Bcl-2/Bcl-xL functions is a major PPAR gamma independent mechanism for apoptosis-inducing effect of troglitazone. In this study, we start from exploring an interesting drugs interaction between TG and celecoxib. Our data indicates 10 µM 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 PPAR gamma activity of TG. In addition, TG-88, a derivative of TG with higher Bcl-2/Bcl-xL inhibitory activity also shows the same potentiation with celecoxib, suggesting the Bcl-2/Bcl-xL functions play an important role in this interaction. 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 PDK1/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 µM is able to potentiate 5 µM 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 PPAR gamma 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.
Ching-Shih Chen (Advisor)
131 p.
Health Sciences, Pharmacy
Troglitazone; Bcl-2; PI3K; Akt; TRAIL; Prostate cancer

Recommended Citations

Citations

  • Chen, K.-F. (2005). Troglitazone: from an insulin sensitizer to a novel class of anti-cancer agent [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1128057928

    APA Style (7th edition)

  • Chen, Kuen-Feng. Troglitazone: from an insulin sensitizer to a novel class of anti-cancer agent. 2005. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1128057928.

    MLA Style (8th edition)

  • Chen, Kuen-Feng. "Troglitazone: from an insulin sensitizer to a novel class of anti-cancer agent." Doctoral dissertation, Ohio State University, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=osu1128057928

    Chicago Manual of Style (17th edition)

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This open access ETD is published by The Ohio State University and OhioLINK.