Pharmaceuticals targeting signaling pathways of endometriosis as potential new medical treatment: A review

Abstract

Endometriosis (EM) is defined as endometrial tissues found outside the uterus. Growth and development of endometriotic cells in ectopic sites can be promoted via multiple pathways, including MAPK/MEK/ERK, PI3K/Akt/mTOR, NF-κB, Rho/ROCK, reactive oxidative stress, tumor necrosis factor, transforming growth factor-β, Wnt/β-catenin, vascular endothelial growth factor, estrogen, and cytokines. The underlying pathophysiological mechanisms include proliferation, apoptosis, autophagy, migration, invasion, fibrosis, angiogenesis, oxidative stress, inflammation, and immune escape. Current medical treatments for EM are mainly hormonal and symptomatic, and thus the development of new, effective, and safe pharmaceuticals targeting specific molecular and signaling pathways is needed. Here, we systematically reviewed the literature focused on pharmaceuticals that specifically target the molecular and signaling pathways involved in the pathophysiology of EM. Potential drug targets, their upstream and downstream molecules with key aberrant signaling, and the regulatory mechanisms promoting the growth and development of endometriotic cells and tissues were discussed. Hormonal pharmaceuticals, including melatonin, exerts proapoptotic via regulating matrix metallopeptidase activity while nonhormonal pharmaceutical sorafenib exerts antiproliferative effect via MAPK/ERK pathway and antiangiogenesis activity via VEGF/VEGFR pathway. N-acetyl cysteine, curcumin, and ginsenoside exert antioxidant and anti-inflammatory effects via radical scavenging activity. Natural products have high efficacy with minimal side effects; for example, resveratrol and epigallocatechin gallate have multiple targets and provide synergistic efficacy to resolve the complexity of the pathophysiology of EM, showing promising efficacy in treating EM. Although new medical treatments are currently being developed, more detailed pharmacological studies and large sample size clinical trials are needed to confirm the efficacy and safety of these treatments in the near future.

Keywords: endometriosis; pathophysiology; pathways; pharmaceuticals; targets; treatments.

Figure 1

Pathophysiology of endometriosis. The schematic diagram was created using BioRender.com. Akt, protein kinase B; ATG, autophagy‐related genes; DC, dendritic cells; E₂, estrogen; ECM, extracellular matrix; ER, estrogen eceptor; ERK extracellular signal‐regulated kinase; FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptors; HIF, hypoxia‐inducible factors; MΦ, macrophages; MAPK, mitogen‐activated protein kinase; MEK, ERK kinase; mTOR, mammalian target of rapamycin; NF‐κB, nuclear factor κB; NK, natural killer; PDGF, platelet‐derived growth factor; PDGFR, platelet‐derived growth factor receptor; PI3K, phosphoinositide 3‐kinases; Rho, Ras homolog family; ROCK, Rho‐associated coiled‐coil kinase; VEGF, vascular endothelial growth factor; TGF, transforming growth factor; TNF, tumor necrosis factor; Treg, regulatory T cells; Wnt, wingless‐type mouse mammary tumor virus integration site family; YAP, Yes‐associated protein