Parthenolide reduces cell proliferation and PGE2 synthesis in human endometriotic stromal cells and inhibits development of endometriosis in murine model

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 561-585-Ovarian & Uterine Function II
Basic/Clinical
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-579
Fuminori Taniguchi*, Eri Takai, Masao Izawa, Naoki Terakawa and Tasuku Harada
Tottori Univ/Fac of Med, Yonago, Japan
Background:  The medical herb feverfew has been used as a folk remedy for the treatment of fevers, migraine and rheumatoid arthritis. Parthenolide is the primary bioactive compound in feverfew having its anti-inflammatory and anti-tumor properties. We showed previously that tumor necrosis factor (TNF) α and interleukin (IL)-8 enhanced mitogenic activity, and TNFα upregulates IL-8 expression in human endometriotic stromal cells (ESCs).

Objective: We evaluated the effect of parthenolide on the proliferation of endometriotic cells and the development of endometriosis-like lesions using the murine model system.

Materials and Methods:  Institutional Review Boards of Tottori University Faculty of Medicine approved this project. With their informed consent, we recruited 20 women with ovarian endometriomas who had regular ovulatory cycles. Ectopic endometrial tissue from ovarian endometriomas was collected, and ESCs were isolated from these tissues. ESCs were pretreated with parthenolide (5µM) and exposed to TNFα (1ng/ml). After TNFα addition, IL-8 and COX-2gene expression were evaluated by real-time RT-PCR. IL-8 and PGE2 protein expression were determined by ELISA. Cell proliferation after TNFα addition was assessed by BrdU-ELISA. Phosphorylation of intracellular signaling molecules was evaluated by Western blot analysis. As a murine endometriosis model, estradiol-treated ovariectomized mice (n=24) were injected intraperitoneally with the endometrial fragments of donor mice. After 4 weeks of parthenolide treatment (10mg/kg), the extent of endometriosis-like lesions was evaluated. Gene expression and proliferative activity in these lesions was assessed by real time RT-PCR and Ki67 immunohistochemical staining, respectively.

Results: With parthenolide pretreatment, TNFα-induced IL-8 gene and protein expression in ESCs were significantly diminished. TNFa-induced COX-2 expression and PGE2 synthesis were also inhibited. Adding parthenolide repressed BrdU incorporation into ESCs. Pretreatment with parthenolide inhibited TNFa-induced IkB phosphorylation in ESCs, whereas ERK1/2, p38MAPK, Akt, and JNK1/2 phosphorylation was insignificant. Administering parthenolide significantly reduced the total number of murine endometriosis-like lesions, the surface area and weight. The expression level of Vegf and Il-6 genes, and the percentage of Ki67 positive cells in the endometriosis-like lesions were decreased in response to parthenolide.

Conclusions: Parthenolide repressed development of endometriosis possibly by suppressing inflammatory peritoneal environment through the NFκB pathway.

Nothing to Disclose: FT, ET, MI, NT, TH

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: KAKENHI (Japan Society for the Promotion of Science Grant-in-Aid)@(to F. T.; 21592098)