The effects of MK2206 and chloroquine combination therapy on endometriosis.

Autophagy may be required for regrowth of endometriosis.

Key Points

Highlight:

• This group suggests 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.     

Importance:

• Previous findings suggested that MK2206 (AKT inhibitor) may induce autophagy, suggesting the inhibition of autophagy is a promising target for endometriosis.
• Chloroquine, an anti-malarial drug, and an autophagy inhibitor are approved by the FDA.
• Therefore, this group suggested that treatment with chloroquine with MK2206 may have potential applications in endometriosis.

What’s done here:

• Evaluated the effects of autophagy inhibition individually and in combination with MK2206 on cell growth and/or cell regrowth of endometriotic stromal cells in vitro.
• Knockdown of the autophagy-related genes: ATG13, Beclin-1, and ATG12
• Pharmacologic agents: chloroquine, bafilomycin A1, or 3-methyalanine
• Measured the effects of combined treatment with MK2206 and chloroquine on endometriotic implants in a mouse xenograft model of endometriosis.

Results:

• Combined treatment with MK2206 and chloroquine markedly reduced cell growth and regrowth after discontinuation of treatment in endometriotic stromal cells in vitro.
• Autophagy inhibition by either ATG13, Beclin-1, or ATG12 gene knockdown only affected regrowth of endometriotic stromal cells after a 72-h discontinuation of the combined treatment.
• Only the combinations treatment significantly reduced the size of endometriotic implants in a mouse xenograft model of endometriosis in vivo.

Limitations:

• Further studies are required to determine whether long-term inhibition of autophagy prevents recurrence of endometriosis after discontinuation of drug treatment.
• Also, more investigation regarding side effects of the combination treatment on the endometrium is highly needed.

Lay Summary

Endometriosis affects approximately 10% of women of reproductive age. A high recurrence rate after medical treatment with or without surgery is a significant clinical problem for patients with endometriosis. Establishment of a complete cure for patients with endometriosis awaits new targets and strategies.

Dr. Michel Canis group from Université Clermont Auvergne previously found that MK2206 (AKT inhibitor) may induce autophagy, suggesting the inhibition of autophagy is promising for targeting endometriosis. Therefore, they hypothesized that treatment with chloroquine, an FDA approved autophagy inhibitor, with MK2206 may have potential applications in endometriosis.

To test their hypothesis, this group evaluated the effects of autophagy inhibition individually and in combination with MK2206 on cell growth and regrowth of endometriotic stromal cells. In vitro experiment, they found the combined treatment with MK2206 and chloroquine markedly reduced cell growth and regrowth after discontinuation of therapy in endometriotic stromal cells.

This group also measured the in vivo effects of combined treatment. Consistent with in vitro data, only the combination treatment significantly reduced the size of endometriotic implants in a mouse xenograft model of endometriosis.

Therefore, this group suggests 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. However further studies are required to determine whether long-term inhibition of autophagy prevents recurrence of endometriosis after discontinuation of drug treatment. Also, more investigations regarding side effects of the combination treatment are highly needed.

Research Source: https://www.ncbi.nlm.nih.gov/pubmed/29457968