Overcoming paclitaxel resistance in uterine endometrial cancer using a COX-2 inhibitor

Abstract

Cyclooxygenase (COX)-2 inhibitors have been reported to potentially modulate the resistance of cancer cells to chemotherapeutic drugs by affecting multidrug resistance 1 (MDR1) expression. In the present study, we investigated the association between COX-2 and MDR1 expression in endometrial cancers and evaluated the effects of the COX-2 inhibitor, etodolac, in combination with paclitaxel on paclitaxel-resistant endometrial cancer cells. The relationship between COX-2 and MDR1 mRNA expression was examined by quantitative PCR in 36 endometrial cancer specimens. The paclitaxel-resistant cell line OMC-2P was established from OMC-2 cells. Paclitaxel (1 µg/ml) with or without etodolac (10 µg/ml) was added to OMC-2 and OMC-2P cells, and COX-2 and MDR1 mRNA expression levels were examined. The concentration of prostaglandin E2 (PGE2) in the supernatant of each cell line was examined by enzyme-linked immunosorbent assay. The function of MDR1 was determined by intracellular accumulation of rhodamine 123 using flow cytometry, and the concentration of intracellular paclitaxel was determined by high-performance liquid chromatography. We found a positive relationship between COX-2 and MDR1 mRNA expression in endometrial cancer. Both COX-2 mRNA expression and PGE2 production were elevated in resistant OMC-2P cells when compared to non-resistant OMC-2 cells. Additionally, MDR1 mRNA expression was markedly upregulated in OMC-2P cells. In OMC-2 cells, COX-2 and MDR1 mRNA levels were significantly upregulated by paclitaxel treatment and downregulated by co-administration with etodolac. In OMC-2P cells, COX-2 mRNA expression was also significantly upregulated by paclitaxel treatment and tended to be downregulated by co-administration with etodolac. Moreover, co-administration of paclitaxel and etodolac suppressed the induction of MDR1 mRNA. Rhodamine 123 efflux was increased in OMC-2P cells when compared to the efflux in the OMC-2 cells and was increased in response to paclitaxel treatment. Co-administration of paclitaxel and etodolac in both cell lines resulted in decreased rhodamine 123 efflux. The actual concentration of intracellular paclitaxel in OMC-2P cells was significantly lower than that in OMC-2 cells treated with paclitaxel alone and was significantly increased after co-administration of paclitaxel and etodolac. These findings suggest that paclitaxel resistance may be associated with COX-2 and MDR1 expression in cancer cells. Co-administration of COX-2 inhibitors and paclitaxel may have a key role in modulating or overcoming paclitaxel resistance in endometrial cancers.

The Effect and Mechanism of Celecoxib in Hypoxia-Induced Survivin Up-Regulation in HUVECs

“…Cox-2 and PGE 2 are up-regulated in many cancer tissues and can be suppressed by Cox-2 inhibitors [37]. The present study found that expression of PGE 2 and Cox-2 were elevated simultaneously under hypoxia.…”

The Role of Eicosanoids in Gynecological Malignancies

“…Overall there is a theme that inhibition of COX pathways leads to potentiation of chemotherapeutic treatment in multiple gynecological malignancies including ovarian (Li et al, 2012a;Li et al, 2013), uterine (Hasegawa et al, 2013;Reader et al, 2019) and vulvar (Kim et al, 2009a). Additional studies are warranted to explore the role of and the mechanism behind adding inhibition of prostanoid receptors to chemotherapy and other treatment modalities in order to conserve potential antineoplastic eicosanoid activities for development of novel treatments for gynecologic malignancies.…”

“…Dual inhibition of COX-2 and mTORC1 signaling markedly reduces endometrial cancer progression (Daikoku et al, 2014). Paclitaxel resistance may be associated with COX-2 and multidrug resistance 1 (MDR1) expression, an efflux pump that can transport a wide range of compounds including chemotherapy out of the cell, in endometrial cancer (Hasegawa et al, 2013). Co-administration of COX-2 inhibitor etodolac with paclitaxel leads to a decrease in MDR1 expression which may enhance accumulation of MDR1 substrates such as paclitaxel thus leading to an increase in paclitaxel sensitivity (Hasegawa et al, 2013).…”

“…Paclitaxel resistance may be associated with COX-2 and multidrug resistance 1 (MDR1) expression, an efflux pump that can transport a wide range of compounds including chemotherapy out of the cell, in endometrial cancer (Hasegawa et al, 2013). Co-administration of COX-2 inhibitor etodolac with paclitaxel leads to a decrease in MDR1 expression which may enhance accumulation of MDR1 substrates such as paclitaxel thus leading to an increase in paclitaxel sensitivity (Hasegawa et al, 2013). However, recently Cummings, et al using laser capture microdissection, whole genome expression analysis and liquid chromatography-tandem mass spectrometry, did not show an increase in COX isoform expression nor PGE 2 /PGF 2a levels in neoplastic endometrium compared to sample matched epithelial tissue (Cummings et al, 2019).…”

Enforced expression of miR-101 enhances cisplatin sensitivity in human bladder cancer cells by modulating the cyclooxygenase-2 pathway

“…Cyclooxygenase-2 (COX-2) is a key regulator of inflammation-producing prostaglandins and thus could be involved in inflammation-associated cancer development (15). Increased COX-2 expression has been found in a number of apoptosis-resistant cancer cells (16); therefore, COX-2 may be a potential target in the reversal of this apoptosis resistance. The expression of COX-2 has been shown to be modulated by several mechanisms, including the action of miRNA (17).…”