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Biochemical Pharmacology (v.74, #9)


The complex etiology of multiple sclerosis by Raymond J. Winquist; Ann Kwong; Ravi Ramachandran; Jugnu Jain (pp. 1321-1329).
Multiple sclerosis is a demyelinating disease which is presumed to be a consequence of infiltrating lymphocytes autoreactive to myelin proteins. This is substantiated by several lines of clinical evidence and supported by correlative studies in preclinical models. The development of new therapeutics for MS has been guided by this perspective; however, the pathogenesis of MS has proven to be quite complex as observations exist which question the role of autoreactive lymphocytes in the etiology of MS. In addition the current immunomodulatory therapeutics do not prevent most patients from progressing into more serious forms of the disease. The development of truly transformational therapeutics for MS will likely require a broad assault that expands beyond the concept of MS being an autoimmune disease.

Keywords: Abbreviations; MS; multiple sclerosis; DTH; delayed type hypersensitivity; RRMS; relapsing, remitting multiple sclerosis; EAE; experimental autoimmune encephalomyelitis; MRI; magnetic resonance imaging; EDSS; expanded disability status scale; MBP; myelin basic protein; PLP; proteolipid protein; MOG; myelin oligodendrocyte glycoprotein; Th-1; T helper cell type-1; OCBs; oligoclonal bands; CSF; cerebrospinal fluid; IFN-β; beta-interferon; IFN-γ; gamma-interferon; Th-2; T helper cell type-2; VLA; very late antigen; MHC; major histocompatibility complex; HLA; histocompatibility leukocyte antigen; Th-17; T cells producing IL-17; PBMCs; peripheral blood mononuclear cells; qRT-PCR; quantitative real time-polymerase chain reaction; MSRV/HERV-W; MS-associated retrovirus/human endogenous retrovirus W; HHV-6; human herpesvirus-6; EBV; Epstein–Barr virus; SIP-1; sphingosine-1-phosphate; CB; 1; cannabinoid receptor type 1; CB; 2; cannabinoid receptor type 2; ROCK; rho-associated kinase; Kv; voltage gated potassium channel; T; em; memory effector T cells; HSCT; hematopoietic (bone or bone-marrow derived) stem cell transplantation; hESCs; human embryonic stem cellsMultiple sclerosis; Inflammation; Autoimmune; EAE; Demyelination; Myelin


Sulfated polymannuroguluronate, a novel anti-AIDS drug candidate, inhibits HIV-1 Tat-induced angiogenesis in Kaposi's sarcoma cells by Cong-Xiao Lu; Jing Li; Yong-Xu Sun; Xin Qi; Qing-Juan Wang; Xian-Liang Xin; Mei-Yu Geng (pp. 1330-1339).
Kaposi's sarcoma (KS), a neoplasm often associated with iatrogenic and acquired immunosuppression, is characterized by prominent angiogenesis. Angiogenic factors released from KS and host cells and HIV viral products—the protein Tat are reported to be involved in angiogenesis. Mounting evidence further suggests that multiple angiogenic activities of Tat contribute to AIDS-associated Kaposi's sarcoma (AIDS-KS). Herein, we report that sulfated polymannuroguluronate (SPMG), a novel anti-AIDS drug candidate now undergoing phase II clinical trial, significantly eliminated Tat-induced angiogenesis in SLK cells both in vitro and in vivo. SPMG significantly and dose-dependently inhibits proliferation, migration, and tube formation by SLK cells. SPMG also dramatically arrested Tat-driven KDR phosphorylation and blocked the interaction between Tat and integrin β1, thus inhibiting the phosphorylation of the downstream kinases of FAK, paxillin and MAPKs. In addition, SPMG was noted to block the release of bFGF and VEGF from ECM. All these collectively favor an issue that SPMG functions as a promising therapeutic against Tat-induced angiogenesis and pathologic events relevant to AIDS-KS, which adds novel mechanistic profiling to the anti-AIDS action of SPMG.

Keywords: Abbreviations; AIDS; acquired immune deficiency syndrome; AIDS-KS; AIDS-associated Kaposi's sarcoma; bFGF; basic fibroblast growth factor; ECM; extracellular matrix; ERK; extracellular-signal regulated kinase; FAK; focal adhesion kinase; GAGs; glycosaminoglycans; GST-Tat; glutathione; S; -transferase-Tat; HIV-1; human immunodeficiency virus type 1; JNK; c-jun amino-terminal kinase; KS; Kaposi's sarcoma; MAPK; mitogen-activated protein kinase; PBS; phosphate-buffered saline; RGD; arginine-glycine-aspartic acid; SPMG; sulfated polymannuroguluronate; Tat; transactivator of transcription; VEGF; vascular endothelial growth factor; KDR; kinase insert domain-containing receptorSulfated polymannuroguluronate; HIV-1; Tat; AIDS; Kaposi's sarcoma; Angiogenesis


The anticancer agent prodigiosin induces p21WAF1/CIP1 expression via transforming growth factor-beta receptor pathway by Vanessa Soto-Cerrato; Francesc Viñals; James R. Lambert; Ricardo Pérez-Tomás (pp. 1340-1349).
The anticancer agent prodigiosin has been shown to act as an efficient immunosuppressant, eliciting cell cycle arrest at non-cytotoxic concentrations, and potent proapoptotic and antimetastatic effects at higher concentrations. Gene expression profiling of MCF-7 cells after treatment with a non-cytotoxic concentration of prodigiosin showed that expression of the p21WAF1/CIP1 gene, a negative cell cycle regulator was induced. In this study, we show that prodigiosin induces p21 expression leading to cell cycle blockade. Subsequently, we attempted to elucidate the molecular mechanisms involved in prodigiosin-mediated p21 gene expression. We demonstrate that prodigiosin induces p21 in a p53-independent manner as prodigiosin induced p21 in cells with both mutated and dominant negative p53. Conversely, the transforming growth factor-beta (TGF-β) pathway has been found to be necessary for p21 induction. Prodigiosin-mediated p21 expression was blocked by SB431542, a TGF-β receptor inhibitor. Nevertheless, this pathway alone is not enough to induce p21 expression. The TGF-β family member (nonsteroidal anti-inflammatory drug)-activated gene 1/growth differentiation factor 15 (NAG-1) may activate this pathway, as it has previously been suggested to signal through the TGF-β pathway and is overexpressed in response to prodigiosin treatment. We show that NAG-1 colocalizes with TGF-β receptor type I, suggesting a possible interaction between them. Taken together, these results suggest the TGF-β pathway is required for induction of p21 expression after prodigiosin treatment of MCF-7 cells.

Keywords: Abbreviations; GSK-3β; glycogen synthase kinase-3 beta; FBS; fetal bovine serum; IC; 25; inhibitory concentration 25; MAPK; mitogen-activated protein kinase; MTT; methyl-thiazole-tetrazolium; NAG-1/GDF-15; (nonsteroidal anti-inflammatory drug)-activated gene 1/growth differentiation factor 15; p21; p21; WAF1/CIP1; PG; prodigiosin; TGF-β; transforming growth factor-beta; TGF-βRI; TGF-β receptor type IProdigiosin; p21; Cell cycle arrest; TGF-β; NAG-1; Breast cancer


Identification of novel bradykinin-potentiating peptides (BPPs) in the venom gland of a rattlesnake allowed the evaluation of the structure–function relationship of BPPs by Claudiana L. Gomes; Katsuhiro Konno; Isaltino M. Conceição; Danielle Ianzer; Norma Yamanouye; Benedito C. Prezoto; Marina T. Assakura; Gandhi Rádis-Baptista; Tetsuo Yamane; Robson A. Santos; Antonio C.M. de Camargo; Mirian A.F. Hayashi (pp. 1350-1360).
Aiming to extend the knowledge about the diversity of bradykinin-potentiating peptides (BPPs) and their precursor proteins, a venom gland cDNA library from the South American rattlesnake ( Crotalus dursissus terrificus, Cdt) was screened. Two novel homologous cDNAs encoding the BPPs precursor protein were cloned. Their sequence contain only one single longer BPP sequence with the typical IPP-tripeptide, and two short potential BPP-like molecules, revealing a unique structural organization. Several peptide sequences structurally similar to the BPPs identified in the precursor protein from Cdt and also from others snakes, were chemically synthesized and were bioassayed both in vitro and in vivo, by means of isolated smooth muscle preparations and by measurements of blood pressure in anaesthetized rats, respectively. We demonstrate here that a pyroglutamyl residue at the N-terminus with a high content of proline residues, even with the presence of a IPP moiety characteristic of typical BPPs, are not enough to determine a bradykinin-potentiating activity to these peptides. Taken together, our results indicate that the characterization of the BPPs precursor proteins and identification of characteristic glutamine residues followed by proline-rich peptide sequences are not enough to predict if these peptides, even with a pyroglutamyl residue at the N-terminus, will present the typical pharmacological activities described for the BPPs.

Keywords: Abbreviations; BPPs; Bradykinin-potentianting peptides; ACE; angiotensin I-converting enzyme; Bk; bradykinin; Bj; Bothrops jararaca; Cdt; Crotalus durissus terrificus; Ahb; Gloydius blomhoffii; (former; Agkistrodon halys blomhoffii; ); Tg; Trimeresurus gramineus; Tf; Protobothrops flavoviridis; (former; Trimeresurus flavoviridis; ); ORF; open reading frame; IPP-tripeptide; Ile-Pro-Pro tripeptide; ISP-tripeptide; Ile-Ser-Pro tripeptide;


YS 51, 1-(β-naphtylmethyl)-6,7-dihydroxy-1,2,3,4,-tetrahydroisoquinoline, protects endothelial cells against hydrogen peroxide-induced injury via carbon monoxide derived from heme oxygenase-1 by Ja Myung Heo; Hye Jung Kim; Yu Mi Ha; Min Kyu Park; Young Jin Kang; Young Soo Lee; Han Geuk Seo; Jae Heun Lee; Hye Sook Yun-Choi; Ki Churl Chang (pp. 1361-1370).
Oxidative stress plays an important role in the pathophysiology of several vascular diseases such as atherosclerosis, and great attention has been placed on the protective role of heme oxygenase-1 (HO-1) for vasculature against oxidant-induced injury. We tested whether the protective effects of YS 51, 1-(β-naphtyl-methyl)-6,7-dihydroxy-1,2,3,4,-tetrahydroisoquinoline, against hydrogen peroxide (H2O2)-induced cell injury is associated with HO-1 activity in bovine aortic endothelial cells (BAEC). YS 51 increased HO-1 expression and activity in concentration-dependent manners (10–100μM) and time-dependent manners (1, 3, 6, 18h), which were correlated well with its protective effect against H2O2-induced injury. Zinc protoporphyrin IX (ZnPP IX), a HO inhibitor, significantly inhibited the effect of YS 51 (50μM). In contrast, [Ru(CO)3(Cl)2]2 (CORM-2, a CO releasing molecule) but not bilirubin protected against H2O2-induced injury. Oxyhemoglobin (HbO2) used as a CO scavenger significantly inhibited the protective effect of both YS 51 and CORM-2. Furthermore, both YS 51 and CORM-2 significantly reduced H2O2-induced intracellular reactive oxygen species (ROS) production; however, this was counteracted by ZnPP IX, HbO2 and deferoxamine. We found evidence for the involvement of PI3/Akt kinase and ERK1/2 pathways in HO-1 induction by YS-51. Taken together, we conclude that CO is, at least, responsible for the YS 51-mediated protective action of endothelial cells against oxidant stress via HO-1 gene induction, involving the activation of the PI3/Akt and ERK1/2 kinase pathways. Thus, YS 51 may be useful in oxidative stress-induced vascular disorders.

Keywords: Abbreviations; HO; heme oxygenase; ROS; reactive oxygen species; H; 2; O; 2; hydrogen peroxide; CO; carbon monoxide; PI3 kinase; phosphatidylinositol 3 kinase; CORM-2; CO releasing molecule; [Ru(CO); 3; (Cl); 2; ]; 2; tricarbonyldichloro-ruthenium dimmer; DPPH; 1,1-dipheny-2-picrylhydrazyl; DCFH-DA; 2′,7′-dichlorofluorescin diacetate; DCF; 2′,7′-dichlorofluorescin; NF-κB; nuclear factor kappa-B; iNOS; increase inducible nitric oxide synthase; ZnPP IX; zinc protoporphyrin IXHeme oxygenase-1; Carbon monoxide; Reactive oxygen species; Oxidative injury; Antioxidant; YS 51; Endothelial cell


Effects of anti-inflammatory drugs on proliferation, cytotoxicity and osteogenesis in bone marrow mesenchymal stem cells by Je-Ken Chang; Ching-Ju Li; Shun-Cheng Wu; Ching-Hua Yeh; Chung-Hwan Chen; Yin-Chih Fu; Gwo-Jaw Wang; Mei-Ling Ho (pp. 1371-1382).
Nonsteroidal anti-inflammatory drugs (NSAIDs) were found to suppress proliferation and induce cell death in cultured osteoblasts, and steroids were found to decrease the osteogenesis potential of mesenchymal stem cells. In this study, we further tested the effects of anti-inflammatory drugs (AIDs) on the functions of bone marrow mesenchymal stem cells (BMSCs). The BMSCs from mice (D1-cells) and humans (hBMSCs) were treated with dexamethasone (10−7 to 10−6M), cyclooxygenase-2 (COX-2) selective NSAIDs (10−6 to 10−5M) and non-selective NSAIDs (10−5 to 10−4M). Drug effects on proliferation, cell cycle kinetics, cytotoxicity and mRNA and protein expressions of cell cycle regulators were tested. The osteogenesis potential of D1-cells were evaluated by testing mRNA expressions of type Iα collagen and osteocalcin 2–8 days after treatments, and testing mineralization 1–3 weeks after treatments. The results showed that all the tested drugs suppressed proliferation and arrested cell cycle of D1-cells, but no significant cytotoxic effects was found. Prostaglandin E1, E2 and F2α couldn’t rescue the effects of AIDs on proliferation. The p27kip1 expression was up-regulated by indomethacin, celecoxib and dexamethasone in both D1-cells and hBMSCs. Higher concentrations of indomethacin and dexamethasone also up-regulated p21Cip1/Waf1 expression in hBMSCs, and so did celecoxib on D1-cells. Expressions of cyclin E1 and E2 were down-regulated by these AIDs in D-cells, while only cyclin E2 was down-regulated by dexamethasone in hBMSCs. All the tested NSAIDs revealed no obvious detrimental effects on osteogenic differentiation of D1-cells. These results suggest that the proliferation suppression of AIDs on BMSCs may act via affecting expressions of cell cycle regulators, but not prostaglandin-related mechanisms.

Keywords: Anti-inflammatory drugs; Mesenchymal stem cells; Proliferation; Cell cycle regulators; Cytotoxicity; Osteogenesis


Modulation of glyceraldehyde 3 phosphate dehydrogenase activity and tyr-phosphorylation of Band 3 in human erythrocytes treated with ferriprotoporphyrin IX by Fausta Omodeo-Salè; Lucia Cortelezzi; Elena Riva; Elisa Vanzulli; Donatella Taramelli (pp. 1383-1389).
Erythrocyte glyceraldehyde-3-phosphate dehydrogenase (G3PD), is a glycolytic enzyme normally inhibited upon binding to the anion transporter Band 3 and activated when free in the cytosol. We have previously reported that ferric protoporphyrin IX (FP) enhances G3PD activity in human erythrocytes (RBC). This could be due to two mechanisms considered in this work: Band 3 tyrosine phosphorylation or oxidative damage of specific G3PD binding sites in the membrane. In both cases binding of G3PD to the membrane would be prevented, leading to the enhancement of G3PD activity. Here, we show that FP induces a dose- and time-dependent phosphorylation of tyrosine 8 and 21 of Band 3, as confirmed by the recruitment of SHP2 phosphatase to the membrane. It appears that Band 3 phosphorylation is due to the oxidation of critical sulfydryl groups of a membrane phosphatase (PTP). Data on membrane localization, Mg2+ dependence, sensitivity to thiol oxidizing agents and protection by N-acetylcysteine (NAC) and DTT strongly suggest the involvement of PTP1B, the major PTP of human RBC associated to and acting on Band 3. However, FP activates G3PD even when Band 3 phosphorylation is inhibited, therefore phosphorylation is not the mechanism underlying G3PD activation by FP. The capacity of NAC of counteracting the stimulatory activity of FP, supports the hypothesis that FP might induce the oxidative damage of specific G3PD binding sites in the membrane, causing the displacement of the enzyme into the cytosol and/or the release from its binding site and therefore its activation.

Keywords: Glyceraldehyde 3 phosphate dehydrogenase; Haem; Erythrocyte; Ferriprotoporphyrin IX; Band 3


Preparation and characterization of dialkylphosphoryl-obidoxime conjugates, potent anticholinesterase derivatives that are quickly hydrolyzed by human paraoxonase (PON1192Q) by J. Stenzel; F. Worek; P. Eyer (pp. 1390-1400).
The potential of the most active pyridinium-4-aldoximes, such as obidoxime and trimedoxime, to reactivate phosphorylated acetylcholinesterase is not fully exploited because of inevitable formation of phosphoryloximes (POXs) with extremely high anticholinesterase activity. Hence, a topochemical equilibrium is expected at the active site, with the freshly reactivated enzyme being rapidly re-inhibited by POX produced during reactivation. In the present study, dimethylphosphoryl-, diethylphosphoryl-, and diisopropyl-obidoxime conjugates were generated and isolated in substance. Their inhibition rate of acetylcholinesterase from human red cell membranes was by a factor of 2250, 480 and 600 higher than that observed with paraoxon-methyl, paraoxon-ethyl, and diisopropyl phosphorofluoridate, respectively. All three POXs were hydrolyzed by human paraoxonase (PON1), with the alloenzyme PON1192Q being about 50-fold more active than PON1192R. The rate of hydrolysis, yielding obidoxime, was 1:6:0.03 for the three POXs, respectively. The rate of non-enzymic degradation, yielding obidoxime mononitrile, was similar with the three POXs and showed a high dependency on the reaction temperature (activation energy 83kJ/mol), while enzymic hydrolysis required less energy (16kJ/mol). To determine POX-hydrolase activity, we preferred a reaction temperature of 20°C to reduce the noise of spontaneous degradation. A plot of POX-hydrolase versus salt-stimulated paraoxonase activity showed a highly discriminating power towards the PON1Q192R alloenzymes, which may be based on repulsive forces of the quaternary nitrogen atoms of the protonated arginine subtype and the bisquaternary POXs. It is concluded that the pharmacogenetic PON1Q192R polymorphism may be another contributor to the large variability of susceptible subjects seen in obidoxime-treated patients.

Keywords: Abbreviations; AChE; acetylcholinesterase; DEP-obidoxime; O; ,; O; ′-diethylphosphoryl-obidoxime; DMP-obidoxime; O; ,; O; ′-dimethylphosphoryl-obidoxime; DIP-obidoxime; O; ,; O; ′-diisopropylphosphoryl-obidoxime; DFP; diisopropyl phosphorofluoridate; MOPS; 3-(; N; -morpholino)propanesulfonate; OP; organophosphorus compounds; 2-PAM; pyridinium-2-aldoxime; PON; paraoxonase; POX; phosphoryloxime; TMB-4; trimedoximeAcetylcholinesterase; Paraoxonase; Phenotypes; Phosphoryl oximes; Obidoxime; Kinetic constants


Differential regulation on human skin fibroblast by α1 adrenergic receptor subtypes by Leonor Sterin-Borda; César Furlan; Betina Orman; Enri Borda (pp. 1401-1412).
Alpha 1 adrenoceptor (α1-AR) regulation of DNA synthesis was studied in human neonatal foreskin fibroblast. Saturation assay with a specific radioligand for α1 adrenergic [3H]-prazosin revealed two saturated and specific binding sites with high or low affinity. Competitive binding assay with different antagonist subtypes, defined pharmacologically three major types of α1-AR. The α1-AR agonists (from 1×10−10 to 1×10−4M) triggered a biphasic action on DNA synthesis reaching maximal stimulation at 1×10−9M and maximal inhibition at 1×10−6M. Prazosin, abolished the stimulatory (pA2: 9.24) and inhibitory (pA2: 8.80) actions of α1-AR agonists. The α1-AR stimulation resulted in the activation of phosphoinositide turnover (InsP) via phospholipase C (PLC) involving calcium/calmodulin (CaM) and nitric oxide synthase (NOS) that correlates with the DNA synthesis increment; whereas the inhibition resulted in a decrease of cyclic AMP (cAMP) accumulation via adenylate cyclase inhibition. The potency displayed by the specific antagonists tested in binding, DNA synthesis, InsP and NOS at low agonist concentration suggests that they can be elicited by the activation of the same receptor (α1B-AR subtype); while the decrement in DNA synthesis and cAMP at high concentration account by the activation of α1D-AR coupled to Gi protein. Non-functional α1A-AR in neonatal human foreskin fibroblast was observed. Results suggest that the expression of α1-AR subtypes on human skin fibroblast may differentially activate signaling pathways that modulate physiological response of the cells.

Keywords: Human fibroblast; Skin fibroblast; α; 1; Adrenergic subtypes; Phosphoinositides; Cyclic AMP; Binding of [; 3; H]-prazosin


Tamoxifen protects male mice nigrostriatal dopamine against methamphetamine-induced toxicity by Mélanie Bourque; Bin Liu; Dean E. Dluzen; Thérèse Di Paolo (pp. 1413-1423).
The selective estrogen receptor modulator tamoxifen and estradiol were shown to protect nigrostriatal dopamine concentration loss by methamphetamine in female mice whereas male mice were protected only by tamoxifen. The present study examined the protective properties of tamoxifen in male mice on several nigrostriatal dopaminergic markers and body temperature. Intact male mice were administered 12.5 or 50μg tamoxifen 24h before methamphetamine treatment. Basal body temperatures of male mice remained unchanged by the tamoxifen treatment. Methamphetamine reduced striatal dopamine and its metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid concentrations, striatal and substantia nigra dopamine and vesicular monoamine transporter specific binding as well substantia nigra dopamine and vesicular monoamine transporter mRNA levels and increased striatal preproenkephalin mRNA levels. These methamphetamine effects were not altered by 12.5μg tamoxifen except for increased striatal dopamine metabolites and turnover. Tamoxifen at 50μg reduced the methamphetamine effect on striatal dopamine concentration, dopamine transporter specific binding and prevented the increase in preproenkephalin mRNA levels; in the substantia nigra tamoxifen prevented the decrease of dopamine transporter mRNA levels. The present results show a tamoxifen dose-dependent prevention of loss of various dopaminergic markers against methamphetamine-induced toxicity in male mice. Since this is the only known hormonal protection of male mice against methamphetamine toxicity, these findings provide important new information on specific parameters of nigrostriatal dopaminergic function preserved by tamoxifen.

Keywords: Abbreviations; DA; dopamine; DAT; dopamine transporter; DOPAC; 3,4-dihydroxyphenylacetic acid; HVA; homovanillic acid; MA; methamphetamine; MAO; monoamine oxidase; MPTP; 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; PD; Parkinson's disease; PPE; preproenkephalin; SN; substantia nigra; TMX; tamoxifen; VMAT2; vesicular monoamine transporter2; [; 125; I]-RTI-121; 3β-(4-[; 125; I]iodophenyl)tropane-2β-carboxylic acid isopropyl ester; [; 3; H]-TBZ-OH; [; 3; H]dihydrotetrabenazineDopamine; Striatum; Substantia nigra; Neuroprotection; Parkinson's disease


Selective serotonin reuptake inhibitors—A new modality for the treatment of lymphoma/leukaemia? by Christian Schuster; Nora Fernbach; Uwe Rix; Giulio Superti-Furga; Marion Holy; Michael Freissmuth; Harald H. Sitte; Veronika Sexl (pp. 1424-1435).
Selective serotonin reuptake inhibitors (SSRIs) have recently been reported to specifically kill malignant cells of B-lymphoid origin, i.e., cells derived from Burkitt lymphoma. Accordingly, SSRIs have been proposed as lead compounds in the development of new approaches to the treatment of lymphoma/leukaemia. Here we attempted to dissect the underlying signaling pathways by comparing susceptible and resistant cell lines. However, we found that all cell lines investigated underwent apoptotic cell death when exposed to SSRI concentrations exceeding 10μM regardless of whether the cell lines were derived from B- (e.g., Namalwa, Ramos, Daudi, RL7), T-lymphoid tumors (e.g., Molt-4, Jurkat, CCRF-CEM) or other sources. The structure–activity relationship readily distinguished the pro-apoptotic and growth inhibitory effect of SSRIs from their eponymous action (blockage of the serotonin transporter): acetylation of the SSRIs fluvoxamine and paroxetine abrogated the ability of these compounds to inhibit 5HT-uptake, but did not impair their cytotoxic action. Based on these data we conclude that (i) SSRIs inhibit growth of transformed cells, but that (ii) this effect is neither specific for malignant cells nor specific for any particular cellular subset. (iii) The pro-apoptotic effect of SSRIs (at μM concentrations) is unrelated to their principal pharmacological action, i.e., inhibition of serotonin uptake (at nM concentrations). SSRIs or improved versions thereof are therefore unlikely to represent useful lead compounds for inducing apoptosis in B-cell derived tumors: the underlying mechanism is not confined to any specific cell lineage.

Keywords: Abbreviations; Annexin V-APC-Cy7; annexin V-allophycocyanin-cyanin7; DAT; dopamine transporter; ESI-MS; electron spray ionization mass spectrometry; FACS; fluorescence activated cell sorting; FCS; fetal calf serum; HPLC; high performance liquid chromatography; SERT; serotonin transporter; SSRI; selective serotonin reuptake inhibitorsSelective serotonin reuptake inhibitors; Burkitt lymphoma; Leukaemia; Serotonin transporter; Selective killing; Apoptosis
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