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

Reprod Biomed Online. 2019 Oct;39(4):556-568. doi: 10.1016/j.rbmo.2019.05.019. Epub 2019 May 31.


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.

MeSH terms

  • Adult
  • Aminobenzoates / pharmacology
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Caspase 3 / drug effects
  • Caspase 3 / metabolism
  • Cell Survival / drug effects
  • Cells, Cultured
  • Doxorubicin / pharmacology
  • Drug Resistance / physiology*
  • Endometriosis / pathology*
  • Endometrium / drug effects*
  • Endometrium / metabolism
  • Endometrium / pathology*
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Female
  • Humans
  • Necrosis / pathology
  • Oligopeptides / pharmacology
  • Oxadiazoles / pharmacology
  • Peritoneal Diseases / pathology*
  • Sorafenib / pharmacology
  • Stromal Cells / drug effects
  • Stromal Cells / metabolism
  • Stromal Cells / pathology
  • Young Adult


  • Aminobenzoates
  • GSK690693
  • Oligopeptides
  • Oxadiazoles
  • auristatin
  • Doxorubicin
  • Sorafenib
  • Caspase 3