5,7‐Dimethoxyflavone induces apoptotic cell death in human endometriosis cell lines by activating the endoplasmic reticulum stress pathway

Abstract

Endometriosis is a reproductive disorder characterized by the dislocation of endometrial tissues. Approximately 5–20% of women at their reproductive age are diagnosed with endometriosis, which causes chronic pain and infertility. Here, we demonstrated that the bioactive flavonoid, 5,7‐dimethoxyflavone (DMF), exhibited antiproliferative and apoptotic effects in VK2/E6E7 and End1/E6E7 cells which were established from vaginal and endocervical tissue taken from a premenopausal woman undergoing hysterectomy for endometriosis. DMF treatment significantly elevated DNA fragmentation resulting in apoptotic cell death in both cell lines. Furthermore, DMF induced loss of mitochondrial membrane potential, dysregulation of intracellular calcium level, and ROS production, which accelerate apoptosis. Additionally, DMF modulated the expression of the signaling molecules related to cell survival and endoplasmic reticulum stress in VK2/E6E7 and End1/E6E7 cells. Overall, DMF may ameliorate endometriosis and can be a potential alternative to hormonal and surgical therapy for endometriosis treatment.

Endometriosis and Phytoestrogens: Friends or Foes? A Systematic Review

“…Finally, the compound was shown to inactivate the intracellular phosphatidylinositol 3-kinase (PI3K)/protein kinase B signaling pathway in a dose-dependent manner from 5 to 100 μM. Similar results and the same biological mechanisms were reported for chyrisin by Park et al [ 75 ], actually testing 5,7-Dimethoxyflavone (DMF), a methylated form of chrysin extracted from Kaempferia parviflora (KP). The methylation of flavonoids has been demonstrated to greatly increase their absorption and bioavailability.…”

“…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.…”

“…Various mechanisms have been proposed to explain this in vitro action including the alteration of cell cycle proteins, the activation/inactivation of regulatory pathways, modification of ROS levels. Two considerations should be done in relation to the in vitro results obtained: 1. among the 22 published studies, nine were written by the same Chinese group [ 50 , 55 , 61 , 66 , 67 , 68 , 69 , 75 , 76 ]. Therefore, confirmatory findings by independent groups need to be obtained.…”

Insight into Potential Anticancer Activity of Algal Flavonoids: Current Status and Challenges

“…In a study, dimethoxyflavone induced apoptosis in endometrioma cells by inhibiting PI3K/AKT and ERK1/2 signaling pathways, activating ER-stress response proteins and MAPK proteins, JNK and p38, increasing the production of ROS and calcium in high levels which led to disruption of mitochondrial membrane potential while inactivating the PI3K/MAPK pathways [65].…”