The serotonin transporter (SLC6A4) is present in B-cell clones of diverse malignant origin: probing a potential anti-tumor target for psychotropics
| Autor: | Meredith, E. J., Holder, M. J., Chamba, A., Challa, A., Drake-Lee, A., Bunce, C. M., Drayson, M. T., Pilkington, G., Blakely, R. D., Dyer, M. J., Barnes, N. M., Gordon, J. |
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| Jazyk: | angličtina |
| Rok vydání: | 2005 |
| Předmět: |
Apoptosis/drug effects
Fluoxetine/pharmacology N-Methyl-3 4-methylenedioxyamphetamine/pharmacology Serotonin Plasma Membrane Transport Proteins/*analysis/drug effects/physiology Psychotropic Drugs/*pharmacology Clomipramine/pharmacology Cell Line Tumor P-Glycoprotein/analysis Humans Proto-Oncogene Proteins c-bcl-2/analysis/physiology Fenfluramine/pharmacology Burkitt Lymphoma/*chemistry/drug therapy Antineoplastic Agents/*pharmacology Lymphoma B-Cell/*chemistry/drug therapy |
| Popis: | Following our previous description of the serotonin transporter (SERT) acting as a conduit to 5-hydroxytryptamine (5-HT)-mediated apoptosis, specifically in Burkitt's lymphoma, we now detail its expression among a broad spectrum of B cell malignancy, while exploring additional SERT substrates for potential therapeutic activity. SERT was readily detected in derived B cell lines with origins as diverse as B cell precursor acute lymphoblastic leukemia, mantle cell lymphoma, diffuse large B cell lymphoma, and multiple myeloma. Concentration and timecourse kinetics for the antiproliferative and proapoptotic activities of the amphetamine derivatives fenfluramine (an appetite suppressant) and 3,4-methylenedioxymethamphetamine (MDMA; "Ecstasy") revealed them as being similar to the endogenous indoleamine. A tricyclic antidepressant, clomipramine, instead mirrored the behavior of the selective serotonin reuptake inhibitor fluoxetine, both being effective in the low micromolar range. A majority of neoplastic clones were sensitive to one or more of the serotonergic compounds. Dysregulated bcl-2 expression, either by t(14;18)(q32;q21) translocation or its introduction as a constitutively active transgene, provided protection from proapoptotic but not antiproliferative outcomes. These data indicate a potential for SERT as a novel anti-tumor target for amphetamine analogs, while evidence is presented that the seemingly more promising antidepressants are likely impacting malignant B cells independently of the transporter itself. Faseb Journal |
| Databáze: | OpenAIRE |
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