Enterolactone promotes Efficacy of Gemcitabine on Epithelial Ovarian Cancer and ameliorates Gut dysbacteriosis

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Epithelial ovarian cancer (EOC) is a deadly malignant tumor that impacts the female reproductive system, ranking third in incidence after cervical and endometrial cancers and first in mortality rate among these three major tumors. The conventional treatments include chemotherapy, radiotherapy, and surgery, but their effectiveness is very limited and their side effects are serious. This situation calls for alternative therapeutic strategies, such as drug combinations, to enhance treatment efficacy and at the same time reduce adverse consequences. Previous research has demonstrated the inhibitory effects of enterolactone (ENL) on EOC by mechanisms such as inhibiting malignant angiogenesis. Gemcitabine (Gem) is a chemotherapeutic agent commonly used for the treatment of EOC. In this study, we aimed to explore the combined inhibitory effects of ENL and Gem on EOC. We examined the combined inhibitory effects of ENL and Gem on EOC proliferation, migration, and invasion, as well as the in vitro and in vivo modulation of the related proteins AKT/Bax/MMP-9/VEGFR2. We used tube formation and zebrafish neovascularization assays to assess the anti-angiogenic activity and established mouse cancer models to assess the hypothesized synergistic inhibitory effects on EOC between the drugs. ENL and Gem demonstrated significant synergistic inhibitory effects on cancer cell proliferation, migration, angiogenesis and AKT/Bax/MMP-9/VEGFR2 modulation. In animal experiments, the combined use of ENL and Gem also synergistically inhibited tumor growth and in the meantime markedly reduced the side effects of Gem. ENL ameliorated gut dysbacteriosis of ovarian cancer animals, which significantly enhanced the synergistic anti-cancer effect of ENL and Gem.

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