Chemosensitivity and chemoresistance in endometriosis – differences for ectopic versus eutopic cells
Creators
- 1. Competence Centre on Health Technologies, Tartu, Estonia
- 2. Tartu University Hospital's Women's Clinic, Tartu, Estonia
- 3. Institute of Chemistry, University of Tartu, Tartu, Estonia
Description
RESEARCH QUESTION:
Endometriosis is a common gynaecological disease defined by the presence of endometrium-like tissue outside the uterus. This complex disease, often accompanied by severe pain and infertility, causes a significant medical and socioeconomic burden; hence, novel strategies are being sought for the treatment of endometriosis. Here, we set out to explore the cytotoxic effects of a panel of compounds to find toxins with different efficiency in eutopic versus ectopic cells, thus highlighting alterations in the corresponding molecular pathways.
DESIGN:
The effect on cellular viability of 14 compounds was established in a cohort of paired eutopic and ectopic endometrial stromal cell samples from 11 patients. The biological targets covered by the panel included pro-survival enzymes, cytoskeleton proteins, the proteasome and the cell repair machinery.
RESULTS:
Protein kinase inhibitors GSK690693, ARC-775 and sorafenib, proteasome inhibitor bortezomib, and microtubule-depolymerizing toxin monomethyl auristatin E were more effective in eutopic cells. In contrast, 10 µmol/l of the anthracycline toxin doxorubicin caused cellular death in ectopic cells more effectively than in eutopic cells. The large-scale sequencing of mRNA isolated from doxorubicin-treated and control cells indicated different survival strategies in eutopic versus ectopic endometrium.
CONCLUSIONS:
Overall, the results confirm evidence of large-scale metabolic reprogramming in endometriotic cells, which underlies the observed differences in sensitivity towards toxins. The enhanced efficiency of doxorubicin interfering with redox equilibria and/or DNA repair mechanisms pinpoints key players that can be potentially used to selectively target ectopic lesions in endometriosis.
Files
Lavogina et al. 2019_manuscript.pdf
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Additional details
Funding
- SARM – Endometrial and embryonic genomics, searching for biomarkers in assisted reproduction (short title: Search for Assisted Reproduction Markers) 324509
- European Commission
- WIDENLIFE – Widening the Scientific Excellence for Studies on Women’s and Fetal Health and Wellbeing 692065
- European Commission
- MOMENDO – Molecular Mechanisms of Endometriosis 691058
- European Commission