Dopamine targets cycling B cells independent of receptors/transporter for oxidative attack: Implications for non-Hodgkin’s lymphoma

September 5, 2006
103 (36) 13485-13490

Abstract

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.

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Acknowledgments

This work was supported by the Leukaemia Research Fund (U.K.), a University of Birmingham Medical School Studentship, and Swedish Cancer Association Grant 3171 GSD (to A.R.).

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Information & Authors

Information

Published in

Go to Proceedings of the National Academy of Sciences
Go to Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences
Vol. 103 | No. 36
September 5, 2006
PubMed: 16938864

Classifications

Submission history

Received: May 30, 2006
Published online: September 5, 2006
Published in issue: September 5, 2006

Keywords

  1. apoptosis
  2. oxidative stress
  3. Parkinson’s disease
  4. Bcl-2
  5. monoamines

Acknowledgments

This work was supported by the Leukaemia Research Fund (U.K.), a University of Birmingham Medical School Studentship, and Swedish Cancer Association Grant 3171 GSD (to A.R.).

Authors

Affiliations

Elizabeth J. Meredith
Medical Research Council Centre for Immune Regulation, Division of Immunity and Infection, The Medical School, University of Birmingham, Vincent Drive, Birmingham B15 2TT, United Kingdom;
Michelle J. Holder
Medical Research Council Centre for Immune Regulation, Division of Immunity and Infection, The Medical School, University of Birmingham, Vincent Drive, Birmingham B15 2TT, United Kingdom;
Anders Rosén
Department of Biomedicine and Surgery, University of Linköping, SE-581 85 Linköping, Sweden;
Adrian Drake Lee
Ear, Nose, and Throat (ENT) Department, University Hospital, Edgbaston, Birmingham B15 2TH, United Kingdom;
Martin J. S. Dyer
Medical Research Council Toxicology Unit, Leicester University, Leicester LE1 9HN, United Kingdom; and
Nicholas M. Barnes
Division of Neuroscience, University of Birmingham, Birmingham B15 2TT, United Kingdom
Medical Research Council Centre for Immune Regulation, Division of Immunity and Infection, The Medical School, University of Birmingham, Vincent Drive, Birmingham B15 2TT, United Kingdom;

Notes

††
To whom correspondence should be addressed. E-mail: [email protected]
Communicated by George Klein, Karolinska Institutet, Stockholm, Sweden, July 18, 2006
E.J.M. and M.J.H. contributed equally to this work.
**N.M.B. and J.G. contributed equally to this work.
Author contributions: E.J.M., N.M.B., and J.G. designed research; E.J.M. and M.J.H. performed research; A.R., A.D.L., and M.J.S.D. contributed new reagents/analytic tools; A.R. analyzed data; and J.G. wrote the paper.

Competing Interests

Conflict of interest statement: No conflicts declared.

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    Dopamine targets cycling B cells independent of receptors/transporter for oxidative attack: Implications for non-Hodgkin’s lymphoma
    Proceedings of the National Academy of Sciences
    • Vol. 103
    • No. 36
    • pp. 13261-13560

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