Selective cyclooxygenase inhibitors increase paclitaxel sensitivity in taxane-resistant ovarian cancer by suppressing P-glycoprotein expression.
10.3802/jgo.2013.24.3.273
- Author:
Jung Pil LEE
1
;
Ho Suap HAHN
;
Soo Jin HWANG
;
Ji Young CHOI
;
Jong Sup PARK
;
In Ho LEE
;
Tae Jin KIM
Author Information
1. Department of Obstetrics and Gynecology, Ellemedi Women's Hospital, Seoul, Korea.
- Publication Type:Original Article
- Keywords:
Chemosensitizer;
Cyclooxygenase inhibitor;
Ovarian cancer;
Paclitaxel;
P-glycoprotein
- MeSH:
Apoptosis;
Cell Death;
Cyclooxygenase Inhibitors;
Dinoprostone;
Flow Cytometry;
Ovarian Neoplasms;
P-Glycoprotein;
Paclitaxel;
Prostaglandin-Endoperoxide Synthases;
Tetrazolium Salts;
Thiazoles
- From:Journal of Gynecologic Oncology
2013;24(3):273-279
- CountryRepublic of Korea
- Language:English
-
Abstract:
OBJECTIVE: The purpose of this study was to investigate whether selective cyclooxygenase (COX) inhibitors promote paclitaxel-induced apoptosis in taxane-resistant ovarian cancer cells by suppressing MDR1/P-glycoprotein (P-gp) expression. METHODS: Taxane-resistant ovarian cancer cells were cultured with paclitaxel alone or combined with a selective COX inhibitors. The expression patterns of MDR1/P-gp and the ability of COX inhibitors to inhibit growth of taxane-resistant ovarian cancer cells were measured. The efficacy of prostaglandin E2 (PGE2) supplementation was measured to evaluate the mechanisms involved in suppressing MDR1 gene expression. RESULTS: P-gp was upregulated in taxane-resistant ovarian cancer cells compared to paired paclitaxel-sensitive ovarian cancer cells. An 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that selective COX inhibitors significantly enhanced the cytotoxic effects of paclitaxel in taxane-resistant ovarian cancer cells via a prostaglandin-independent mechanism. These increased apoptotic effects were further verified by measuring an increased percentage of cells in sub-G1 stage using flow cytometry. Selective COX inhibitors suppressed MDR1 and P-gp expression. Moreover, combined treatment with paclitaxel and selective COX inhibitors increased poly (ADP-ribose) polymerase (PARP) cleavage in taxane-resistant ovarian cancer cells. CONCLUSION: Selective COX inhibitors significantly promote paclitaxel-induced cell death in taxane-resistant ovarian cancer cells in a prostaglandin-independent manner. COX inhibitors could be potent therapeutic tools to promote paclitaxel sensitization of taxane-resistant ovarian cancers by suppressing MDR1/P-gp, which is responsible for the efflux of chemotherapeutic agents.
