Darja Lavogina1, Külli Samuel2, Arina Lavrits3, Alvin Meltsov2, Deniss Sõritsa4, Ülle Kadastik5, Maire Peters6, Ago Rinken7, Andres Salumets8. 1. Competence Centre on Health Technologies Tartu, Estonia; Institute of Chemistry, University of Tartu Tartu, Estonia. Electronic address: darja.lavogina@ut.ee. 2. Competence Centre on Health Technologies Tartu, Estonia. 3. Competence Centre on Health Technologies Tartu, Estonia; Department of Cell Biology, Institute of Molecular and Cell Biology, University of Tartu Tartu, Estonia. 4. Competence Centre on Health Technologies Tartu, Estonia; Department of Obstetrics and Gynaecology, Institute of Clinical Medicine, University of Tartu Tartu, Estonia; Elite Clinic Tartu, Estonia. 5. Tartu University Hospital's Women's Clinic Tartu, Estonia. 6. Competence Centre on Health Technologies Tartu, Estonia; Department of Obstetrics and Gynaecology, Institute of Clinical Medicine, University of Tartu Tartu, Estonia. 7. Institute of Chemistry, University of Tartu Tartu, Estonia. 8. Competence Centre on Health Technologies Tartu, Estonia; Department of Obstetrics and Gynaecology, Institute of Clinical Medicine, University of Tartu Tartu, Estonia; Department of Biomedicine, Institute of Biomedicine and Translational Medicine, University of Tartu Tartu, Estonia; Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Abstract
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.
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.
Authors: Darja Lavogina; Helen Lust; Maris-Johanna Tahk; Tõnis Laasfeld; Hans Vellama; Naila Nasirova; Markus Vardja; Kattri-Liis Eskla; Andres Salumets; Ago Rinken; Jana Jaal Journal: Biosensors (Basel) Date: 2022-03-25