Tamoxifen and its metabolites induce mitochondrial membrane depolarization and caspase-3 activation in equine neutrophils.
Abstract: Neutrophils participate in innate immunity as the first line of host defence against microorganisms. However, persistent neutrophil activity and delayed apoptosis can be harmful to surrounding tissues; this problem occurs in diverse inflammatory diseases, including asthma-affected horses. Previous studies in horses with acute lung inflammation indicated that treatment with tamoxifen (TX), a selective oestrogen receptor modulator, produces a significant decrease in bronchoalveolar lavage fluid (BALF) neutrophil content. The aim of this study was to investigate the effect of tamoxifen and its metabolites (N-desmethyltamoxifen and endoxifen) on the mitochondrial membrane potential assay by flow cytometry, and the activation of effector caspase-3 through immunoblotting, in peripheral blood neutrophils obtained from healthy horses (n = 5). Results show that tamoxifen, N-desmethyltamoxifen and endoxifen depolarize the mitochondrial membrane and activate caspase-3 in healthy equine neutrophils in vitro. These findings suggest that tamoxifen and its metabolites may activate the intrinsic apoptotic pathway in equine neutrophils. However, more studies are necessary to further explore the signalling pathways of these drugs in the induction of apoptosis.
© 2020 The Authors. Veterinary Medicine and Science Published by John Wiley & Sons Ltd.
Publication Date: 2020-06-17 PubMed ID: 32558352PubMed Central: PMC7738725DOI: 10.1002/vms3.316Google Scholar: Lookup
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- Journal Article
- Research Support
- Non-U.S. Gov't
Summary
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The research study is exploring the effects of tamoxifen and its by-products on the immune response of horses, specifically targeting the mitochondrial activity of neutrophils, the body’s first line of defense against infections.
Objective of the Study
- The main aim of the study was to determine how tamoxifen and its by-products (N-desmethyltamoxifen and endoxifen) impact the mitochondrial membrane potential. This was explored through two targeted methodologies – flow cytometry, which studies cell characteristics, and immunoblotting, used in protein detection.
Importance of Neutrophils in Immunity
- Neutrophils are vital participants in the innate immune response, serving as the first line of defense against microorganisms.
- Persistent neutrophil activity or delayed apoptosis, the programmed cell death, can lead to harmful effects on surrounding tissues. This issue is common in various inflammatory diseases such as those seen in asthma-afflicted horses.
Role of Tamoxifen
- Tamoxifen previously has been used in treating horses afflicted with acute lung inflammation, where it significantly decreased the bronchoalveolar lavage fluid’s (BALF) neutrophil content.
- Thus, the study aimed to further explore tamoxifen’s role, broadening the scope to include its metabolites – N-desmethyltamoxifen and endoxifen.
Conclusions and Scope for Further Research
- The study found that tamoxifen and its associated metabolites did indeed depolarize the mitochondrial membrane and activate a protein known as caspase-3 within healthy equine neutrophils, in vitro (in a controlled environment outside a living organism).
- This suggests tamoxifen and its metabolites could stimulate the intrinsic apoptotic pathway within these neutrophils, potentially helping control excessive inflammation in horses by encouraging programmed cell death.
- More research needs to be conducted to fully understand the mechanisms through which tamoxifen and its metabolites induce apoptosis.
Cite This Article
APA
Albornoz A, Morales N, Uberti B, Henriquez C, Burgos RA, Alarcon P, Moran G.
(2020).
Tamoxifen and its metabolites induce mitochondrial membrane depolarization and caspase-3 activation in equine neutrophils.
Vet Med Sci, 6(4), 673-678.
https://doi.org/10.1002/vms3.316 Publication
Researcher Affiliations
- Department of Pharmacology, Faculty of Veterinary Sciences, Universidad Austral de Chile, Valdivia, Chile.
- Department of Pharmacology, Faculty of Veterinary Sciences, Universidad Austral de Chile, Valdivia, Chile.
- Graduate School, Faculty of Veterinary Sciences, Universidad Austral de Chile, Valdivia, Chile.
- Department of Clinical Veterinary Sciences, Faculty of Veterinary Sciences, Universidad Austral de Chile, Valdivia, Chile.
- Department of Pharmacology, Faculty of Veterinary Sciences, Universidad Austral de Chile, Valdivia, Chile.
- Department of Pharmacology, Faculty of Veterinary Sciences, Universidad Austral de Chile, Valdivia, Chile.
- Department of Pharmacology, Faculty of Veterinary Sciences, Universidad Austral de Chile, Valdivia, Chile.
- Department of Pharmacology, Faculty of Veterinary Sciences, Universidad Austral de Chile, Valdivia, Chile.
MeSH Terms
- Animals
- Anti-Asthmatic Agents / pharmacology
- Caspase 3 / immunology
- Female
- Flow Cytometry / veterinary
- Horses / immunology
- Immunity, Innate / drug effects
- Immunoblotting / veterinary
- Male
- Mitochondrial Membranes / drug effects
- Mitochondrial Membranes / physiology
- Neutrophils / drug effects
- Neutrophils / immunology
- Tamoxifen / analogs & derivatives
- Tamoxifen / pharmacology
References
This article includes 23 references
- Borlone C, Morales N, Henriquez C, Folch H, Olave C, Sarmiento J, Uberti B, Moran G. In Vitro effects of tamoxifen on equine neutrophils.. Res Vet Sci 2017 Feb;110:60-64.
- Bruijnzeel PL, Uddin M, Koenderman L. Targeting neutrophilic inflammation in severe neutrophilic asthma: can we target the disease-relevant neutrophil phenotype?. J Leukoc Biol 2015 Oct;98(4):549-56.
- Budtz PE. Role of proliferation and apoptosis in net growth rates of human breast cancer cells (MCF-7) treated with oestradiol and/or tamoxifen.. Cell Prolif 1999 Oct;32(5):289-302.
- Cameron DA, Keen JC, Dixon JM, Bellamy C, Hanby A, Anderson TJ, Miller WR. Effective tamoxifen therapy of breast cancer involves both antiproliferative and pro-apoptotic changes.. Eur J Cancer 2000 May;36(7):845-51.
- Corriden R, Hollands A, Olson J, Derieux J, Lopez J, Chang JT, Gonzalez DJ, Nizet V. Tamoxifen augments the innate immune function of neutrophils through modulation of intracellular ceramide.. Nat Commun 2015 Oct 13;6:8369.
- Degterev A, Boyce M, Yuan J. A decade of caspases.. Oncogene 2003 Nov 24;22(53):8543-67.
- Dietze EC, Caldwell LE, Grupin SL, Mancini M, Seewaldt VL. Tamoxifen but not 4-hydroxytamoxifen initiates apoptosis in p53(-) normal human mammary epithelial cells by inducing mitochondrial depolarization.. J Biol Chem 2001 Feb 16;276(7):5384-94.
- El Kebir D, Filep JG. Role of neutrophil apoptosis in the resolution of inflammation.. ScientificWorldJournal 2010 Sep 1;10:1731-48.
- Emert-Sedlak L, Shangary S, Rabinovitz A, Miranda MB, Delach SM, Johnson DE. Involvement of cathepsin D in chemotherapy-induced cytochrome c release, caspase activation, and cell death.. Mol Cancer Ther 2005 May;4(5):733-42.
- Galluzzi L, Kepp O, Trojel-Hansen C, Kroemer G. Mitochondrial control of cellular life, stress, and death.. Circ Res 2012 Oct 12;111(9):1198-207.
- Jackson CA, Berney C, Jefcoat AM, Robinson NE. Environment and prednisone interactions in the treatment of recurrent airway obstruction (heaves).. Equine Vet J 2000 Sep;32(5):432-8.
- Mainguy-Seers S, Picotte K, Lavoie JP. Efficacy of tamoxifen for the treatment of severe equine asthma.. J Vet Intern Med 2018 Sep;32(5):1748-1753.
- Mandlekar S, Kong AN. Mechanisms of tamoxifen-induced apoptosis.. Apoptosis 2001 Dec;6(6):469-77.
- McCracken JM, Allen LA. Regulation of human neutrophil apoptosis and lifespan in health and disease.. J Cell Death 2014;7:15-23.
- Morales N, Henriquez C, Sarmiento J, Uberti B, Moran G. Tamoxifen inhibits chemokinesis in equine neutrophils.. Ir Vet J 2018;71:22.
- Olave C, Alvarez P, Uberti B, Morales N, Henriquez C, Folch H, Sarmiento J, Moran G. Tamoxifen induces apoptosis and inhibits respiratory burst in equine neutrophils independently of estrogen receptors.. J Vet Pharmacol Ther 2019 Mar;42(2):248-254.
- Olave C, Morales N, Uberti B, Henriquez C, Sarmiento J, Ortloff A, Folch H, Moran G. Tamoxifen induces apoptotic neutrophil efferocytosis in horses.. Vet Res Commun 2018 Mar;42(1):57-63.
- Perez B, Henriquez C, Sarmiento J, Morales N, Folch H, Galesio JS, Uberti B, Morán G. Tamoxifen as a new therapeutic tool for neutrophilic lung inflammation.. Respirology 2016 Jan;21(1):112-8.
- Robinson NE. International Workshop on Equine Chronic Airway Disease. Michigan State University 16-18 June 2000.. Equine Vet J 2001 Jan;33(1):5-19.
- Sarmiento J, Perez B, Morales N, Henriquez C, Vidal L, Folch H, Galecio JS, Morán G. Apoptotic effects of tamoxifen on leukocytes from horse peripheral blood and bronchoalveolar lavage fluid.. Vet Res Commun 2013 Dec;37(4):333-8.
- Teng TS, Ji AL, Ji XY, Li YZ. Neutrophils and Immunity: From Bactericidal Action to Being Conquered.. J Immunol Res 2017;2017:9671604.
- Uberti B, Morán G. Role of neutrophils in equine asthma.. Anim Health Res Rev 2018 Jun;19(1):65-73.
- Wang C, Youle RJ. The role of mitochondria in apoptosis*.. Annu Rev Genet 2009;43:95-118.
Citations
This article has been cited 1 times.- Salinas C, Barriga K, Albornoz A, Alarcon P, Quiroga J, Uberti B, Sarmiento J, Henriquez C, Ehrenfeld P, Burgos RA, Moran G. Tamoxifen triggers the in vitro release of neutrophil extracellular traps in healthy horses.. Front Vet Sci 2022;9:1025249.
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