当前位置： SCI文献检索 > GYNECOLOGIC ONCOLOGY期刊下所有文献 > Enhancement of sensitivity to cisplatin by orobol is associated with increased mitochondrial cytochrome c release in human ovarian carcinoma cells.

Enhancement of sensitivity to cisplatin by orobol is associated with increased mitochondrial cytochrome c release in human ovarian carcinoma cells.

Abstract：

OBJECTIVES:Based on our previous report showing that orobol, a potent phosphatidylinositol 4-kinase (PI4K) inhibitor, produced cisplatin (DDP) sensitivity, we have determined the mechanism of orobol-sensitization effect. METHODS AND RESULTS:Orobol produced >2-fold DDP sensitivity in human ovarian carcinoma 2008 cells and its DDP-resistant variant 2008/C13*5.25 cells (C13). Because orobol had no effect on conventional mechanisms such as DDP accumulation or cellular metallothionein and glutathione content, we have focused on the apoptotic signaling pathway. Orobol induced a significant increase in apoptosis in DDP-treated cells, as estimated by frequency of condensed nuclear chromatin with Hoechst 33342 stain, although orobol alone did not have any effect on apoptotic potential. The caspase-3-inhibiting peptide Ac-DEVD-CHO completely inhibited the orobol sensitization effect but did not block DDP cell cytotoxicity per se. Orobol rendered both of these cells resistant to rhodamine 123 (Rh) by more than 2.5-fold, indicating significant decrease of mitochondrial membrane potential (DeltaPsim). Confocal laser microscopy of cells stained with the mitochondria (MT)-specific dye Rh revealed that orobol decreased Rh-fluorescent intensity. Electron microscopy of these cells showed that orobol induced swelling and condensation of MT. Orobol suppressed both naturally expressed and the DDP-induced Bcl-2 expression significantly. Orobol and DDP treatment reduced cytochrome c level in MT determined by Western blot analysis, indicating increased amount of cytochrome c release from MT, whereas orobol alone did not alter the amount of cytochrome c in MT. CONCLUSIONS:These results indicate that orobol produced DDP sensitivity in human ovarian carcinoma cells by inducing apoptosis through the MT-dependent signaling pathway.

journal_name

Gynecol Oncol

journal_title

Gynecologic oncology

authors

Isonishi S,Saitou M,Yasuda M,Ochiai K,Tanaka T

doi

10.1016/s0090-8258(03)00316-0

subject

Has Abstract

pub_date

2003-08-01 00:00:00

pages

413-20

issue

eissn

0090-8258

issn

1095-6859

pii

S0090825803003160

journal_volume

pub_type

杂志文章

在线工具

Enhancement of sensitivity to cisplatin by orobol is associated with increased mitochondrial cytochrome c release in human ovarian carcinoma cells.