Dopamine targets cycling B cells independent of receptors/transporter for oxidative attack: Implications for non-Hodgkin's lymphoma.
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 muM) 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.
Meredith
Elizabeth J
EJ
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.
Holder
Michelle J
MJ
Rosén
Anders
A
Lee
Adrian Drake
AD
Dyer
Martin J S
MJ
Barnes
Nicholas M
NM
Gordon
John
J
D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects* / Q000502:physiology; D002374:Catalase / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D002472:Cell Transformation, Viral; D004298:Dopamine / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004854:Herpesvirus 4, Human / Q000502:physiology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy*; D026901:Membrane Transport Proteins / Q000502:physiology*; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011954:Receptors, Dopamine / Q000145:classification / Q000502:physiology*
D026901:Membrane Transport Proteins; D016877:Oxidants; D019253:Proto-Oncogene Proteins c-bcl-2; D011954:Receptors, Dopamine; D006861:Hydrogen Peroxide; D002374:Catalase; D004298:Dopamine