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Iron In Endometriosis
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Apr 27, 2016, 9:54:02 AM4/27/16
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Kinase signalling pathways in endometriosis: potential targets for non-hormonal therapeutics
Brett D. McKinnon1,2,*, Vida Kocbek1,2, Kostantinos Nirgianakis1,2, Nick A. Bersinger1,2 and Michael D. Mueller1,2
Hum. Reprod. Update (May/June 2016) 22 (3):
doi: 10.1093/humupd/dmv060
First published online: January 5, 2016
1Department of Obstetrics and Gynaecology, Inselspital, Berne University Hospital, Effingerstrasse 102, Berne CH-3010, Switzerland
2Department of Clinical Research, University of Berne, Murtenstrasse 35, Berne CH-3010, Switzerland
↵*Correspondence address. E-mail: brett.m...@dkf.unibe.ch
Received July 31, 2015.
Revision received November 10, 2015.
Accepted December 8, 2015.
Abstract
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.
Key words
inflammation signalling kinase NF kappa B mTOR MAPK microenvironment treatment drugs endometriosis
© The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.p...@oup.com
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"Mimosine, through iron chelation"
"Desferrioxamine (DFO), a well-characterized iron chelator"
"Both reduced proline-directed protein kinase activity to less
than 10% of control after 16 hr treatment."
Mimosine blocks cell cycle progression by chelating iron in
asynchronous human breast cancer cells.
Toxicol Appl Pharmacol. 1996 Aug;139(2):356-64.
Kulp KS, Vulliet PR.
Department of Molecular Biosciences, School of Veterinary Medicine,
University of California, Davis, California 95616-8643, USA.
Mimosine is a toxic nonprotein amino acid that is a major constituent
of the tropical legumes Leucaena and Mimosa.
Mimosine has been shown to cause acute and chronic toxicosis in
livestock fed from forage containing these plants.
Recently, mimosine has been demonstrated to reversibly block cell
cycle progression in mammalian cells in culture.
In this study, we compared the effects of mimosine to desferrioxamine
(DFO), a well-characterized iron chelator, and found that both
chemicals similarly altered cell cycle progression in MDA-MB-453 human
breast cancer cells.
Mimosine (400 microM) and DFO (150 microM) both reduced DNA
synthesis by greater than 90% of control within 4 hr of treatment,
and suppressed total proline-directed protein kinase activity to less than
10% of control after 16 hr treatment.
These effects were antagonized by the addition of iron as ferrous sulfate (250 microM), which is bound to transferrin and imported into the cell via transferrin receptor endocytosis, or as hemin (100 microM), which passes through the cell membrane and releases iron into the cytosol.
After 24 hr treatment with the chelators, a large portion of the available transferrin receptors moved to the cell surface, indicating that the cells were iron-starved.
Our data demonstrate that mimosine, through iron chelation, blocks cell cycle progression in MDA-MB-453 human breast cancer cells.
PMID: 8806853
Who loves ya.
Tom
Jesus Was A Vegetarian!
http://tinyurl.com/2r2nkh
Man Is A Herbivore!
http://tinyurl.com/a3cc3
DEAD PEOPLE WALKING
http://tinyurl.com/zk9fk
Brett D. McKinnon1,2,*, Vida Kocbek1,2, Kostantinos Nirgianakis1,2, Nick A. Bersinger1,2 and Michael D. Mueller1,2
Hum. Reprod. Update (May/June 2016) 22 (3):
doi: 10.1093/humupd/dmv060
First published online: January 5, 2016
1Department of Obstetrics and Gynaecology, Inselspital, Berne University Hospital, Effingerstrasse 102, Berne CH-3010, Switzerland
2Department of Clinical Research, University of Berne, Murtenstrasse 35, Berne CH-3010, Switzerland
↵*Correspondence address. E-mail: brett.m...@dkf.unibe.ch
Received July 31, 2015.
Revision received November 10, 2015.
Accepted December 8, 2015.
Abstract
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.
Key words
inflammation signalling kinase NF kappa B mTOR MAPK microenvironment treatment drugs endometriosis
© The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.p...@oup.com
-----------
"Mimosine, through iron chelation"
"Desferrioxamine (DFO), a well-characterized iron chelator"
"Both reduced proline-directed protein kinase activity to less
than 10% of control after 16 hr treatment."
Mimosine blocks cell cycle progression by chelating iron in
asynchronous human breast cancer cells.
Toxicol Appl Pharmacol. 1996 Aug;139(2):356-64.
Kulp KS, Vulliet PR.
Department of Molecular Biosciences, School of Veterinary Medicine,
University of California, Davis, California 95616-8643, USA.
Mimosine is a toxic nonprotein amino acid that is a major constituent
of the tropical legumes Leucaena and Mimosa.
Mimosine has been shown to cause acute and chronic toxicosis in
livestock fed from forage containing these plants.
Recently, mimosine has been demonstrated to reversibly block cell
cycle progression in mammalian cells in culture.
In this study, we compared the effects of mimosine to desferrioxamine
(DFO), a well-characterized iron chelator, and found that both
chemicals similarly altered cell cycle progression in MDA-MB-453 human
breast cancer cells.
Mimosine (400 microM) and DFO (150 microM) both reduced DNA
synthesis by greater than 90% of control within 4 hr of treatment,
and suppressed total proline-directed protein kinase activity to less than
10% of control after 16 hr treatment.
These effects were antagonized by the addition of iron as ferrous sulfate (250 microM), which is bound to transferrin and imported into the cell via transferrin receptor endocytosis, or as hemin (100 microM), which passes through the cell membrane and releases iron into the cytosol.
After 24 hr treatment with the chelators, a large portion of the available transferrin receptors moved to the cell surface, indicating that the cells were iron-starved.
Our data demonstrate that mimosine, through iron chelation, blocks cell cycle progression in MDA-MB-453 human breast cancer cells.
PMID: 8806853
Who loves ya.
Tom
Jesus Was A Vegetarian!
http://tinyurl.com/2r2nkh
Man Is A Herbivore!
http://tinyurl.com/a3cc3
DEAD PEOPLE WALKING
http://tinyurl.com/zk9fk
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