In vitro and in vivo effects of MK2206 and chloroquine combination therapy on endometriosis: autophagy may be required for regrowth of endometriosis

Sachiko Matsuzaki, Jean-Luc Pouly, Jean‐Luc Pouly, Michel Canis
British journal of pharmacology · 2018 · vol. 175(10) , pp. 1637–1653 · doi:10.1111/bph.14170 · PMID:29457968 · PMC5913408 · W2791340150
article OA: bronze CC0 ⤵ 30 in-corpus citations
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MK2206 and chloroquine combination therapy effectively inhibited endometriotic stromal cell growth and regrowth in vitro, and reduced endometriotic implant size in vivo, suggesting autophagy's role in endometriosis recurrence.

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Abstract

BACKGROUND AND PURPOSE: A high recurrence rate after medical treatment is a major clinical problem for patients with endometriosis. Here, we have evaluated the in vitro effects of combined treatment with MK2206 (an AKT inhibitor) + chloroquine on cell growth and regrowth of endometriotic stromal cells and the in vivo effects on endometriotic implants in a mouse xenograft model of endometriosis. EXPERIMENTAL APPROACH: We evaluated the effects of autophagy inhibition by knockdown of the ATG13, Beclin-1 and ATG12 genes and pharmacological agents (chloroquine, bafilomycin A1 or 3-methyalanine) individually and in combination with MK2206 on cell growth and/or cell regrowth of endometriotic stromal cells in vitro. Furthermore, we evaluated treatment with MK2206 + chloroquine on endometriotic implants in a mouse xenograft model of endometriosis. KEY RESULTS: Combined treatment with MK2206 and chloroquine markedly reduced cell growth and regrowth after discontinuation of treatment in endometriotic stromal cells compared with cells treated with either drug alone. Autophagy inhibition by ATG13, Beclin-1 or ATG12 gene knockdown only affected regrowth of endometriotic stromal cells, but not endometrial stromal cells from the same patients, after a 72 h discontinuation of the combined treatment. Furthermore, combined treatment reduced the size of endometriotic implants, whereas no effects on endometriotic implants treated with either drug alone were observed in a mouse xenograft model of endometriosis. CONCLUSIONS AND IMPLICATIONS: The present findings suggest that a novel strategy for treatment of endometriosis may involve decreasing the number of endometriotic cells that can survive treatment and then preventing regrowth by autophagy inhibition.

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Condition tags

endometriosis

MeSH descriptors

Autophagy Chloroquine Endometriosis Heterocyclic Compounds, 3-Ring Adult Animals Autophagy Cell Proliferation Cell Proliferation Cells, Cultured Chloroquine Chloroquine Disease Models, Animal Drug Therapy, Combination Endometriosis Endometriosis Female Heterocyclic Compounds, 3-Ring Heterocyclic Compounds, 3-Ring Humans

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