Chrysin leads to cell death in endometriosis by regulation of endoplasmic reticulum stress and cytosolic calcium level

Abstract

Chrysin is a natural compound derived from honey, propolis, or passion flowers and has many functional roles, such as antiinflammatory and antiangiogenesis effects. Although endometriosis is a benign gynecological disease, there is a need to identify the pathology and develop a therapy for endometriosis. Elucidating the biological mechanism of chrysin on endometriosis will improve the understanding of endometriosis. In this study, we confirmed the apoptotic effects of chrysin in human endometriotic cells using End1/E6E7 (endocervix‐derived endometriotic cells) and VK2/E6E7 (vaginal mucosa‐derived epithelial endometriotic cells). The results showed that chrysin suppressed the proliferation of endometriosis and induced programmed cell death through changing the cell cycle proportion and increasing the cytosolic calcium level and generation of reactive oxygen species. In addition, chrysin activated endoplasmic reticulum (ER) stress by stimulating the unfolded protein response proteins, especially the 78‐kDa glucose‐regulated protein–PRKR‐like ER kinase (PERK)–eukaryotic translation initiation factor 2α (eIF2α) pathway in both endometriotic cell lines. Furthermore, chrysin inactivated the intracellular phosphoinositide 3‐kinase (PI3K)/protein kinase B (PKB, also known as AKT) signaling pathway in a dose‐dependent manner. Collectively, the results of this study indicated that chrysin induced programmed cell death by activating the ER stress response and inactivating the PI3K signaling pathways in human endometriotic cells.

Endometriosis and Phytoestrogens: Friends or Foes? A Systematic Review

“…A total of 286 studies were initially identified by the search criteria. After applying the selection criteria, a total of 60 trials were included in the systematic review [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 ,…”

“…Finally, Ji and coworkers demonstrated that puerarin can partly suppress estrogen-stimulated proliferation by promoting the recruitment of corepressors to estrogen receptor, as well as limiting that of coactivators, in order to arrest ectopic stromal cells in the G1 phase [ 34 ]. Three studies out of 22 investigated the biological effect of chyrisin, a natural compound derived from honey, propolis, or passion flowers, on human endometrial cells [ 20 , 66 , 75 ]. Although shown to be potent inhibitor of aromatase activity in a free cell assay, chyrisin, daidzein or naringenin could not attenuate aromatase activity in endometrial stromal cells in women with and without endometriosis at any concentration tested.…”

“…Moreover, PE may have poor estrogenic activity in low-estrogen environments such as in menopause and have antiestrogenic activity in high-estrogen environments such as those observed in endometriosis or endometrial cancer [ 16 , 17 ]. Several studies have evaluated the associations between PE and endometriosis risk in animal and human models but the data obtained are quite inconsistent or conflicting [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 ,…”

Chrysin: Perspectives on Contemporary Status and Future Possibilities as Pro-Health Agent

“…It acts through the induction of apoptosis and inhibition of cancer cell migration [43,44]. Its antitumor properties were proven for various malignancies, including prostate cancer (DU 145, PC-3) [45], breast cancer [46], lung cancer (A549), liver cancer (HepG2), colon cancer (SW480) [47] and pancreatic cancer (SW1736, 8505C) [48], and also epidermoid carcinoma (A431) [49], glioblastoma (T98, U251, U87) [50] and human uveal melanoma (SP6.5, M17) [51]. According to the Salama and Allam study [52], chrysin and daidzein exerted anticancer activity against SW620 cells, which was associated with a decrease in the protein expression of p-ERK/ERK and p-AKT/AKT.…”

“…Chrysin may find an application in the treatment of gynecological diseases, such as endometriosis, which may lead to infertility. Research with the use of human endometriotic cells derived from the cervix (End1/E6E7) and vagina (VK2/E6E7) revealed that chrysin suppressed the proliferation and induced apoptosis of these cells by affecting the cell cycle, changing the cytosolic calcium level, affecting the generation of reactive oxygen species and by inactivating the PI3K signaling pathways [45].…”