Abstract
6,8-Diprenylorobol is a flavonoid compound extracted from Cudrania tricuspidata. It has various biological functions, such as inhibiting melanin synthesis and inducting cell death in cancerous cells. In addition, Cudrania tricuspidata is known to be effective in female diseases, and previous studies have shown anticancer effects in cervical cancer, a female reproductive disease. Outside of that, Cudrania tricuspidata has various physiological effects. However, the effect of 6,8-diprenylorobol is not well known in other benign and chronic diseases, even in endometriosis, which commonly arises in the female reproductive tract. In the present study, we determined the inhibitory effects of 6,8-diprenylorobol on the growth of endometriosis VK2/E6E7 and End1/E6E7 cells. Results indicated that 6,8-diprenylorobol suppressed cellular proliferation and increased the disruption of the cell cycle, mitochondrial membrane potential (MMP), generation of reactive oxygen species, and Ca2+ homeostasis in both endometriosis cells. However, the proliferation of normal stromal cells isolated from endometrial tissue was not altered by 6,8-diprenylorobol. The change in Ca2+ levels was estimated in fluo-4- or rhod-2-stained VK2/E6E7 and End1/E6E7 cells after the treatment of the intracellular calcium regulators 2-aminoethoxydiphenyl borate (2-APB) and ruthenium red (RUR) with 6,8-diprenylorobol. A combination of 6,8-diprenylorobol with each regulator decreased the calcium accumulation in endometriosis cells. Furthermore, Western blot analysis indicated that 6,8-diprenylorobol inactivated AKT pathways, whereas it activated P38 MAPK pathways. In addition, 6,8-diprenylorobol decreased mitochondrial respiration, leading to the reduction in ATP production in VK2/E6E7 and End1/E6E7 cells. Collectively, our results suggested that 6,8-diprenylorobol might be a potential therapeutic agent or adjuvant therapy for the management of endometriosis.
Highlights
When VK2/E6E7 and End1/E6E7 cells were treated with 6,8-diprenylorobol, the relative expression of green fluorescence (PCNA), representing a proliferation marker, was reduced by more than 50% compared to vehicle-treated cells (Figure 1C)
We investigated the effects of 6,8-diprenylorobol on mitochondrial function in human endometriosis cells by measuring membrane potential (MMP) (∆ψ) and generating reactive oxygen species (ROS)
It has been reported that several drugs acting on the mitochondrial electron transport chain exhibited anticancer effects [34,35]. While few such studies have been conducted on endometriosis, we confirmed that mitochondrial dysfunction was related to mitochondrial respiration and metabolism through this study
Summary
The cause of endometriosis is not clearly known, but the pathologic retrograde menstruation theory, which explains that backward menstrual blood flow cannot be removed in the abdominal cavity, is usually accepted. This theory is reported to be related. Flavonoids are one of the phytochemical classes, and have several health-enhancing effects, such as antioxidation, anti-cell proliferation, anticancer, and anti-inflammation [6]. There was a study to inhibit cell proliferation by increasing the expression of p53 and inducing apoptosis through the extracellular pathway when the Cudrania tricuspidata stem extract was used to treat cervical cancer [8]. 6,8-diprenylorobol induced apoptosis in colon cancer by activating the P53 apoptotic cell signal pathway [17]. (1) suppression of cellular proliferation; (2) induction of cell cycle arrest; (3) impairment of mitochondrial function and calcium homeostasis; (4) dysregulation of the intracellular signaling pathway (PI3K/AKT signal); and (5) changes in PI3K/AKT protein expression by 6,8-diprenylorobol with inhibitor
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