Systems Pharmacology Model Predicts Zinc and Copper Can Be Repurposed as Endometriosis Therapies

BACKGROUND

Endometriosis is a complex and polygenic disease characterized by the growth of endometrial-like tissue outside the uterus. Associated conditions include pelvic pain and infertility among others. Current treatments of endometriosis are not effective in many patients and are prone of side effects, being laparoscopy the main solution for them. However, laparoscopy is an invasive solution that can negatively affect ovarian reserve among others fertility consequences. Therefore, more effective treatments are needed for inhibiting the disease progression. Some approaches as systems pharmacology can offer new avenues to study complex diseases at a systematic level, allowing us the integration of information at different levels for prioritizing effective therapies.

OBJECTIVE

To use systems pharmacology and in vitro analyses to predict more effective endometriosis treatment among approved drugs on the market for further clinical trials.

STUDY DESIGN

Data-driven discovery study integrating protein-protein interactions, transcriptomics, approved drugs and endometriosis-related gene targets to predict therapies that can be repositioned in endometriosis. An in-silico molecular drug efficacy screening was performed to compare proposed treatments with the current ones. The candidate drugs with the safest clinical profiles were prioritized for in-vitro validation in an endometriosis cell model.

RESULTS

Our endometriosis molecular model showed that the endometriosis progression and the infertility associated are molecularly highly related since they share 210 genes through direct protein-protein interactions from 553 infertility-related and 2,931 progression-related endometriosis genes, an overlap that is higher than randomly expected (p-value = 1.9 × 10⁻¹¹). In addition, these genes are also closer physically interacting in the network than random expectation (z-score = −1.75, p-value = 0.03). Both results highlighted the similar molecular basis of endometriosis progression and infertility associated to endometrium. Leveraging this endometriosis disease network, we have identified sixteen potential candidate drugs, which had a superior molecular efficacy treating the disease genes as they target more endometriosis-related genes (p-value = 0.01) than randomly expected compared with current endometriosis treatments (p-value = 0.97). The drug safety analysis deemed adenine, copper, zinc, NADH, glutathione, and resveratrol as the safest candidate drugs for endometriosis, with no or hardly any clinical side effects. Zinc, copper and resveratrol suppressed endometriosis-related phenotypes in 12Z cells, including cell proliferation, migration, and overexpression of endometriosis-related biomarkers ( ERB , IL-6 and VEGF) .

CONCLUSION

This approach highlights the nutraceutics zinc and copper for having superior molecular efficacy than current endometriosis treatments, no considerable side effects, and the ability to reduce endometriosis cell phenotypes. Long-term clinical trials will be needed to confirm women in vivo effectiveness and provide new treatment opportunities for refractory endometriosis.

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