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Dopamine targets cycling B cells independent of receptors/transporter for oxidative attack: Implications for non-Hodgkin's lymphoma
Division of Immunity and Infection, Medical School, University of Birmingham, Vincent Drive, Birmingham B15 2TT, United Kingdom.
Division of Immunity and Infection, Medical School, University of Birmingham, Vincent Drive, Birmingham B15 2TT, United Kingdom.
Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.ORCID iD: 0000-0001-5082-6423
Ear, Nose, and Throat (ENT) Department, University Hospital, Edgbaston, Birmingham B15 2TH, United Kingdom.
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2006 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 103, no 36, 13485-13490 p.Article in journal (Refereed) Published
Abstract [en]

Human B lymphocytes and derived lines from a spectrum of B cell malignancy were studied for expression of dopaminergic pathway components and for their cytostatic response to the catecholamine and related, potentially therapeutic compounds. Proliferating normal lymphocytes and dividing malignant clones rapidly arrested on exposure to dopamine in the low (=10 µM) micromolar range. The antiparkinsonian drugs L-DOPA and apomorphine (particularly) were similarly antiproliferative. With the exception of D4, dopamine receptors D1-D5 were variably expressed among normal and neoplastic B cell populations, as was the dopamine transporter. Transcripts for D1 and D2 were frequently found, whereas D3 and D5 revealed restricted expression, dopamine transporter was detected in most cases. Nevertheless, pharmacological analysis disclosed that dopamine targeted cycling B cells independent of these structures. Rather, oxidative stress constituted the primary mechanism: the catecholamine's actions being mimicked by hydrogen peroxide and reversed by exogenous catalase, and evidence for the intracellular redox protein thioredoxin contributing protection. Among proliferating clones, growth arrest was accompanied by cell death in populations deplete in antiapoptotic Bcl-2: resting lymphocytes escaping low micromolar dopamine toxicity. Dysregulated bcl-2 expression, although preventing oxidative-induced caspase-dependent apoptosis, by itself conferred only minor protection against dopamine cytostasis. The selective impact of dopamine on lymphocytes that are in active cycle indicates an axis for therapeutic intervention not only in B cell neoplasia but also in lymphoproliferative disturbances generally. Rational tailoring of drug delivery systems already in development for Parkinson's disease could provide ideal vehicles for carrying the oxidative hit directly to the target populations. © 2006 by The National Academy of Sciences of the USA.

Place, publisher, year, edition, pages
2006. Vol. 103, no 36, 13485-13490 p.
Keyword [en]
Apoptosis, Bcl-2, Monoamines, Oxidative stress, Parkinson's disease
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Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-50132DOI: 10.1073/pnas.0605993103OAI: oai:DiVA.org:liu-50132DiVA: diva2:271028
Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2017-12-12

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Rosén, Anders

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