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

Kiyoshi Hasegawa, Kunimi Ishikawa, Satoshi Kawai, Yutaka Torii, Kyoko Kawamura, Rina Kato, Kazuhiko Tsukada, Yasuhiro Udagawa

Research output: Contribution to journalArticle

6 Citations (Scopus)

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 E 2 (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.

Original languageEnglish
Pages (from-to)2937-2944
Number of pages8
JournalOncology reports
Volume30
Issue number6
DOIs
Publication statusPublished - 01-12-2013

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Uterine Neoplasms
Cyclooxygenase 2 Inhibitors
Endometrial Neoplasms
Paclitaxel
Multiple Drug Resistance
Etodolac
Cyclooxygenase 2
Messenger RNA
Rhodamine 123
Prostaglandins E
Cell Line
Down-Regulation

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Hasegawa, K., Ishikawa, K., Kawai, S., Torii, Y., Kawamura, K., Kato, R., ... Udagawa, Y. (2013). Overcoming paclitaxel resistance in uterine endometrial cancer using a COX-2 inhibitor. Oncology reports, 30(6), 2937-2944. https://doi.org/10.3892/or.2013.2790
Hasegawa, Kiyoshi ; Ishikawa, Kunimi ; Kawai, Satoshi ; Torii, Yutaka ; Kawamura, Kyoko ; Kato, Rina ; Tsukada, Kazuhiko ; Udagawa, Yasuhiro. / Overcoming paclitaxel resistance in uterine endometrial cancer using a COX-2 inhibitor. In: Oncology reports. 2013 ; Vol. 30, No. 6. pp. 2937-2944.
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Hasegawa, K, Ishikawa, K, Kawai, S, Torii, Y, Kawamura, K, Kato, R, Tsukada, K & Udagawa, Y 2013, 'Overcoming paclitaxel resistance in uterine endometrial cancer using a COX-2 inhibitor', Oncology reports, vol. 30, no. 6, pp. 2937-2944. https://doi.org/10.3892/or.2013.2790

Overcoming paclitaxel resistance in uterine endometrial cancer using a COX-2 inhibitor. / Hasegawa, Kiyoshi; Ishikawa, Kunimi; Kawai, Satoshi; Torii, Yutaka; Kawamura, Kyoko; Kato, Rina; Tsukada, Kazuhiko; Udagawa, Yasuhiro.

In: Oncology reports, Vol. 30, No. 6, 01.12.2013, p. 2937-2944.

Research output: Contribution to journalArticle

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AU - Hasegawa, Kiyoshi

AU - Ishikawa, Kunimi

AU - Kawai, Satoshi

AU - Torii, Yutaka

AU - Kawamura, Kyoko

AU - Kato, Rina

AU - Tsukada, Kazuhiko

AU - Udagawa, Yasuhiro

PY - 2013/12/1

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