Kinase signalling pathways in endometriosis: potential targets for non-hormonal therapeutics.

Mc Kinnon, Brett; Kocbek, Vida; Nirgianakis, Konstantinos; Bersinger, Nick A.; Mueller, Michael (2016). Kinase signalling pathways in endometriosis: potential targets for non-hormonal therapeutics. Human reproduction update, 22(3), dmv060. Oxford University Press 10.1093/humupd/dmv060

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BACKGROUND Endometriosis, the growth of endometrial tissue outside the uterine cavity, is associated with chronic pelvic pain, subfertility and an increased risk of ovarian cancer. Current treatments include the surgical removal of the lesions or the induction of a hypoestrogenic state. However, a reappearance of the lesion after surgery is common and a hypoestrogenic state is less than optimal for women of reproductive age. Additional approaches are required. Endometriosis lesions exist in a unique microenvironment characterized by increased concentrations of hormones, inflammation, oxidative stress and iron. This environment influences cell survival through the binding of membrane receptors and a subsequent cascading activation of intracellular kinases that stimulate a cellular response. Many of these kinase signalling pathways are constitutively activated in endometriosis. These pathways are being investigated as therapeutic targets in other diseases and thus may also represent a target for endometriosis treatment. METHODS To identify relevant English language studies published up to 2015 on kinase signalling pathways in endometriosis, we searched the Pubmed database using the following search terms in various combinations; 'endometriosis', 'inflammation', 'oxidative stress', 'iron', 'kinase', 'NF kappa', 'mTOR', 'MAPK' 'p38', 'JNK', 'ERK' 'estrogen' and progesterone'. Further citing references were identified using the Scopus database and finally current clinical trials were searched on the clinicaltrials.gov trial registry. RESULTS The current literature on intracellular kinases activated by the endometriotic environment can be summarized into three main pathways that could be targeted for treatments: the canonical IKKβ/NFκB pathway, the MAPK pathways (ERK1/2, p38 and JNK) and the PI3K/AKT/mTOR pathway. A number of pharmaceutical compounds that target these pathways have been successfully trialled in in vitro and animal models of endometriosis, although they have not yet proceeded to clinical trials. The current generation of kinase inhibitors carry a potential for adverse side effects. CONCLUSIONS Kinase signalling pathways represent viable targets for endometriosis treatment. At present, however, further improvements in clinical efficacy and the profile of adverse effects are required before these compounds can be useful for long-term endometriosis treatment. A better understanding of the molecular activity of these kinases, including the specific extracellular compounds that lead to their activation in endometriotic cells specifically should facilitate their improvement and could potentially lead to new, non-hormonal treatments of endometriosis.

Item Type:

Journal Article (Review Article)

Division/Institute:

04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Gynaecology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Endometriose und gynäkologische Onkologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Endometriose und gynäkologische Onkologie

UniBE Contributor:

Mc Kinnon, Brett; Kocbek, Vida; Nirgianakis, Konstantinos; Bersinger, Nick A. and Mueller, Michael

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1355-4786

Publisher:

Oxford University Press

Funders:

[4] Swiss National Science Foundation

Language:

English

Submitter:

Monika Zehr

Date Deposited:

25 Apr 2016 16:45

Last Modified:

06 Jan 2019 02:30

Publisher DOI:

10.1093/humupd/dmv060

PubMed ID:

26740585

Uncontrolled Keywords:

MAPK, NF kappa B, drugs, endometriosis, inflammation, mTOR, microenvironment, signalling kinase, treatment

BORIS DOI:

10.7892/boris.77854

URI:

https://boris.unibe.ch/id/eprint/77854

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