title: The serotonin transporter (SLC6A4) is present in B-cell clones of diverse malignant origin: probing a potential anti-tumor target for psychotropics.
abstract: 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.
authors.affiliation: Division of Immunity and Infection, The Medical School, Birmingham, UK.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Meredith
authors.forename: Michelle J
authors.initials: MJ
authors.lastname: Holder
authors.forename: Anita
authors.initials: A
authors.lastname: Chamba
authors.forename: Anita
authors.initials: A
authors.lastname: Challa
authors.forename: Adrian
authors.initials: A
authors.lastname: Drake-Lee
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Bunce
authors.forename: Mark T
authors.initials: MT
authors.lastname: Drayson
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Pilkington
authors.forename: Randy D
authors.initials: RD
authors.lastname: Blakely
authors.forename: Martin J S
authors.initials: MJ
authors.lastname: Dyer
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Barnes
authors.forename: John
authors.initials: J
authors.lastname: Gordon
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002051:Burkitt Lymphoma / Q000737:chemistry* / Q000188:drug therapy; D045744:Cell Line, Tumor; D002997:Clomipramine / Q000494:pharmacology; D005277:Fenfluramine / Q000494:pharmacology; D005473:Fluoxetine / Q000494:pharmacology; D006801:Humans; D016393:Lymphoma, B-Cell / Q000737:chemistry* / Q000188:drug therapy; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000502:physiology; D011619:Psychotropic Drugs / Q000494:pharmacology*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000032:analysis* / Q000187:drug effects / Q000502:physiology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D011619:Psychotropic Drugs; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D005473:Fluoxetine; D005277:Fenfluramine; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D002997:Clomipramine