Chemosensitivity and chemoresistance in endometriosis - differences for ectopic versus eutopic cells

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Lavoginal , D , Samuel , K , Lavrits , A , Meltsovl , A , Soritsa , D , Kadastik , U , Peters , M , Rinken , A & Salumets , A 2019 , ' Chemosensitivity and chemoresistance in endometriosis - differences for ectopic versus eutopic cells ' , Reproductive BioMedicine Online , vol. 39 , no. 4 , pp. 556-568 .

Title: Chemosensitivity and chemoresistance in endometriosis - differences for ectopic versus eutopic cells
Author: Lavoginal, Darja; Samuel, Kulli; Lavrits, Arina; Meltsovl, Alvin; Soritsa, Deniss; Kadastik, Ulle; Peters, Maire; Rinken, Ago; Salumets, Andres
Contributor: University of Helsinki, HUS Gynecology and Obstetrics
Date: 2019-10
Language: eng
Number of pages: 13
Belongs to series: Reproductive BioMedicine Online
ISSN: 1472-6483
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 microtubuledepolymerizing toxin monomethyl auristatin E were more effective in eutopic cells. In contrast, 10 mu mol/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.
Subject: Cell viability
Eutopic/ectopic endometrial stromal cell
Protein kinase inhibitor
3123 Gynaecology and paediatrics
3111 Biomedicine

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