Abstract
Resveratrol (RSV) is a polyphenolic phytoalexin found in peanuts, grapes, and other plants. Uterine fibroids (UF) are benign growths that are enriched in extracellular matrix (ECM) proteins. In this study, we aimed to investigate the effects of RSV on UF using in vivo and in vitro approaches. In mouse xenograft models, tumors were implanted through the subcutaneous injection of Eker rat-derived uterine leiomyoma cells transfected with luciferase (ELT-3-LUC) in five-week-old female nude (Foxn1nu) mice. When the tumors reached a size of 50–100 mm3, the mice were randomly assigned to intraperitoneal treatment with RSV (10 mg·kg−1) or vehicle control (dimethyl sulfoxide). Tumor tissues were assayed using an immunohistochemistry analysis. We also used primary human leiomyoma cells as in vitro models. Cell viability was determined using the sodium bicarbonate and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The protein expression was assayed using Western blot analysis. The messenger ribonucleic acid (mRNA) expression was assayed using quantitative reverse transcription–polymerase chain reaction (qRT–PCR). Cell apoptosis was assayed using Annexin V-fluorescein isothiocyanate (FITC) and propidium iodide (PI) and Hoechst 33342 staining. RSV significantly suppressed tumor growth in vivo and decreased the proportion of cells showing expression of proliferating cell nuclear antigen (PCNA) and α-smooth muscle actin (α-SMA). In addition, RSV decreased the protein expression of PCNA, fibronectin, and upregulated the ratio of Bax (Bcl-2-associated X) and Bcl-2 (B-cell lymphoma/leukemia 2) in vivo. Furthermore, RSV reduced leiomyoma cell viability, and decreased the mRNA levels of fibronectin and the protein expression of collagen type 1 (COL1A1) and α-SMA (ECM protein marker), as well as reducing the levels of β-catenin protein. RSV induced apoptosis and cell cycle arrest at sub-G1 phase. Our findings indicated the inhibitory effects of RSV on the ELT-3-LUC xenograft model and indicated that RSV reduced ECM-related protein expression in primary human leiomyoma cells, demonstrating its potential as an anti-fibrotic therapy for UF.
Highlights
Benign uterine fibroids (UF), known as myomas or leiomyomas, are the most common neoplasm of the uterus and occur in up to 77% of women by the onset of menopause in the UnitedStates [1,2]
This study identified potentially beneficial inhibitory effects of RSV on UF growth in a mouse xenograft model in vivo, as well as on the proliferation of primary human leiomyoma cells in vitro
In agreement with the results of these studies, our results showed that 100 μM RSV significantly decreased the protein expression of COL1A1, α-smooth muscle actin (α-SMA), and β-catenin, as well as the messenger ribonucleic acid (mRNA) level of FN1 in primary human leiomyoma cells compared to controls in vitro
Summary
Benign uterine fibroids (UF), known as myomas or leiomyomas, are the most common neoplasm of the uterus and occur in up to 77% of women by the onset of menopause in the UnitedStates [1,2]. Women with UF usually suffer from a reduced quality of life due to symptoms such as abnormal uterine bleeding, pelvic pain, frequent urination, and infertility [3,4]. The etiology remains unclear, genetic factors, cytokines, growth factors, steroid hormones (estrogens and progestogens) and/or their receptors, and excessive production of extracellular matrix (ECM) have been reported to play a pivotal role in the development of UF [4]. The major ECM components of UF include fibronectin, collagens, and proteoglycans such as biglycan and fibromodulin [6,7]. Hysterectomy is considered as the only option and the fastest treatment to reduce pain from UF, especially for women with uterine fibroids but a lack of cognition [9]
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