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Reprod Biomed Online. 2019 May 31. pii: S1472-6483(19)30583-8. doi: 10.1016/j.rbmo.2019.05.019. [Epub ahead of print]

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

Author information

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.

KEYWORDS:

Cell viability; Doxorubicin; Endometriosis; Eutopic/ectopic endometrial stromal cell; Protein kinase inhibitor; Toxin

PMID:
31377021
DOI:
10.1016/j.rbmo.2019.05.019

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