Ferulic acid, ligustrazine, and tetrahydropalmatine display the anti-proliferative effect in endometriosis through regulating Notch pathway

Aims: With an ambiguous anti-proliferative mechanism, the combination of ferulic acid, ligustrazine, and tetrahydropalmatine (FLT) shows good anti-endometriosis (EMS) activity. In EMS, the expression of Notch pathway and its role in proliferation are not yet unclear. In this study, we sought to uncover the role of Notch pathway's effect and FLT's anti-proliferative mechanism on EMS proliferation.

Main methods: In autograft and allograft EMS models, the proliferating markers (Ki67, PCNA), Notch pathway, and the effect of FLT on them were detected. Then, the anti-proliferative influence of FLT was measured in vitro. The proliferating ability of endometrial cells was investigated with a Notch pathway activator (Jagged 1 or VPA) or inhibitor (DAPT) alone, or in combination with FLT separately.

Key findings: FLT presented the inhibitory effect on ectopic lesions in 2 EMS models. The proliferating markers and Notch pathway were promoted in ectopic endometrium, but FLT showed the counteraction. Meantime, FLT restrained the endometrial cell growth and clone formation along with a reduction in Ki67 and PCNA. Jagged 1 and VPA stimulated the proliferation. On the contrary, DAPT displayed the anti-proliferating effect. Furthermore, FLT exhibited an antagonistic effect on Jagged 1 and VPA by downregulating Notch pathway and restraining proliferation. FLT also displayed a synergistic effect on DAPT.

Significance: This study indicated that the overexpressing Notch pathway induced EMS proliferation. FLT attenuated the proliferation by inhibiting Notch pathway.