The serotonin transporter (SLC6A4) is present in B-cell clones of diverse malignant origin: probing a potential anti-tumor target for psychotropics.
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.
Meredith
Elizabeth J
EJ
Division of Immunity and Infection, The Medical School, Birmingham, UK.
Holder
Michelle J
MJ
Chamba
Anita
A
Challa
Anita
A
Drake-Lee
Adrian
A
Bunce
Christopher M
CM
Drayson
Mark T
MT
Pilkington
Geoffrey
G
Blakely
Randy D
RD
Dyer
Martin J S
MJ
Barnes
Nicholas M
NM
Gordon
John
J
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
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