An Alternative Medical Approach to Treat Endometriosis?

Molecules known as SRC modulators could be used as a new therapy for endometriosis.

Key Points

Highlights:

• Modulating the activity of a molecule known as SRC-1 could constitute a novel medical approach to treat endometriosis.

Importance:

• This finding could open up a new avenue in the quest of finding a cure for endometriosis.

What's done here:

• Researchers used bufalin as a “tool compound” and analyzed its effects on endometriosis using endometrial stromal cells from women with and without endometriosis and endometrial epithelial and stromal cells grown in the laboratory, as well as mouse models of endometriosis.

Key results:

• Bufalin effectively suppressed the growth of primary human endometrial stromal cells isolated from endometriosis patients compared to women without endometriosis. 
• Bufalin also suppressed the in vitro growth of immortalized human endometrial cells expressing SRC-1, compared to their parental cells.
• Bufalin treatment significantly suppressed the growth of surgically induced endometriotic lesions in mice.
• Bufalin increased the stability and activity of SRC-1 but degraded estrogen receptor-beta in endometriotic lesions.
• Bufalin treatment increased programmed cell death signaling in epithelial cells of endometriotic lesions.
• Bufalin treatment increased the levels of pyroptosis markers and reduced proliferation in stromal cells of endometriotic lesions.
• Bufalin treatment increased the expression of endoplasmic reticulum-stress markers in endometriotic lesions.

Limitations:

• The experiments described in this study were performed on cells grown in the laboratory and in animal models of endometriosis. The results may not be the same in a clinical setting.
• Bufalin was used as a tool compound to assess the effects of modulating SRC activity in the treatment of endometriosis. Other SRC-modulators may not produce the same results as the ones described here.

Lay Summary

Molecules that act on a protein called SRC-1 could constitute a new medical tool to treat endometriosis, according to a study published in the Journal of Endocrinology. 

SRC-1 makes certain parts of DNA more accessible therefore increasing gene expression or the production of certain proteins. SRC-1 can be guided to different areas in the DNA by other molecules and this determines which genes will be more accessible. In endometriosis, estrogen receptors work with SRC-1 and play an essential role in the development of the disease. 

Based on this knowledge, researchers at Baylor College of Medicine, in Huston, Texas, and Dong-A University, College of Medicine in Busan, Korea thought that inhibiting the activity of SRC-1 could be a new potential therapeutic approach for endometriosis. In order to do so, they used a molecule called bufalin. Bufalin is a cardiotonic steroid that was originally isolated from the Chinese toad venom and used in traditional Chinese medicine. 

The team led by Dr. Sang Jun Han treated primary human endometrial stromal cells isolated from women with and without endometriosis and grown in the laboratory with bufalin. They saw that the compound was able to effectively suppress the growth of these cells in women with endometriosis compared to women without endometriosis. The also treated human endometrial epithelial and stromal cells expressing SRC-1 with bufalin and saw that the compound was able to inhibit the growth of these cells compared to cells not expressing SRC-1.

The researchers then moved from cells grown in the laboratory to animal models and tested the effect of bufalin in a mouse model of endometriosis. They showed that bufalin treatment significantly suppressed the growth of endometriotic lesions in animals in which endometriosis was induced surgically.

The researchers then conducted a number of experiments to understand the biological mechanism by which bufalin achieved these effects. 

They found that bufalin increased the stability and activity of SRC-1 but at the same time also promoted the degradation of estrogen receptor-beta in endometriotic lesions, therefore, disrupting the SRC-1 estrogen receptor-beta axis. 

They also found that bufalin treatment increased apoptosis, or programmed cell death signaling in epithelial cells of endometriotic lesions and proptosis in the stromal cells of the lesions. Pyroptosis is an inflammatory form of programmed cell death that normally occurs when cells get infected by pathogens. 

Finally, the researchers found that bufalin treatment increased the levels of stress proteins in endometriotic lesions. 

They concluded that future generations of SRC-modulators similar to bufalin could be used as an alternative for the treatment of endometriosis.

Research Source: https://www.ncbi.nlm.nih.gov/pubmed/29636364