TY - JOUR
T1 - The serotonin transporter (SLC6A4) is present in B-cell clones of diverse malignant origin
T2 - probing a potential antitumor target for psychotropics
AU - Meredith, Elizabeth J.
AU - Holder, Michelle J.
AU - Chamba, Anita
AU - Challa, Anita
AU - Drake-Lee, Adrian
AU - Bunce, Christopher M.
AU - Drayson, Mark T.
AU - Pilkington, Geoff
AU - Blakely, Randy D.
AU - Dyer, Martin J. S.
AU - Barnes, Nicholas M.
AU - Gordon, John
PY - 2005/5
Y1 - 2005/5
N2 - 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.
AB - 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.
KW - 5-hydroxytryptamine
KW - Burkitt's lymphoma
KW - B cell lymphoma
U2 - 10.1096/fj.04-3477fje
DO - 10.1096/fj.04-3477fje
M3 - Article
SN - 0892-6638
VL - 19
SP - 1187-
JO - FASEB Journal
JF - FASEB Journal
IS - 7
ER -