The serotonin transporter (SLC6A4) is present in B-cell clones of diverse malignant origin: probing a potential anti-tumor target for psychotropics.

Meredith EJ, Holder MJ, Chamba A, Challa A, Drake-Lee A, Bunce CM, Drayson MT, Pilkington G, Blakely RD, Dyer MJ, Barnes NM, Gordon J
FASEB J. 2005 19 (9): 1187-9

PMID: 15870169 · DOI:10.1096/fj.04-3477fje

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.

MeSH Terms (14)

Antineoplastic Agents Apoptosis ATP Binding Cassette Transporter, Subfamily B, Member 1 Burkitt Lymphoma Cell Line, Tumor Clomipramine Fenfluramine Fluoxetine Humans Lymphoma, B-Cell N-Methyl-3,4-methylenedioxyamphetamine Proto-Oncogene Proteins c-bcl-2 Psychotropic Drugs Serotonin Plasma Membrane Transport Proteins

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