Selective serotonin reuptake inhibitors directly signal for apoptosis in biopsy-like Burkitt lymphoma cells.
Selective serotonin reuptake inhibitors (SSRIs) are the treatment of choice for clinical depression and a range of anxiety-related disorders. They are well tolerated over extended periods with more than 50 million people worldwide benefiting from their use. Here we show that 3 structurally distinct SSRIs--fluoxetine, paroxetine, and citalopram--act directly on Burkitt lymphoma (BL) cells to trigger rapid and extensive programmed cell death. SSRIs unexpectedly stimulated calcium flux, tyrosine phosphorylation, and down-regulation of the c-myc and nm23 genes in Burkitt lymphoma cells remaining faithful to the biopsy phenotype. Resultant SSRI-induced apoptosis was preceded by caspase activation, poly(ADP-ribose) polymerase-1 (PARP-1) cleavage, DNA fragmentation, a loss of mitochondrial membrane potential, and the externalization of phosphatidylserine, and reversed by the overexpression of bcl-2. Normal peripheral blood mononuclear cells and tonsil B cells, whether resting or stimulated into cycle, were largely resistant to SSRI-induced death as were 5 non-BL lymphoid cell lines tested. We discuss these findings within the context of whether the SSRI class of antidepressants could find future application as potential therapeutics for the highly aggressive and-because of its association with AIDS-increasingly more common Burkitt lymphoma.
Serafeim
Adamantios
A
Medical Research Council Centre for Immune Regulation, School of Biosciences, University of Birmingham, Birmingham, United Kingdom.
Holder
Michelle J
MJ
Grafton
Gillian
G
Chamba
Anita
A
Drayson
Mark T
MT
Luong
Quang T
QT
Bunce
Christopher M
CM
Gregory
Christopher D
CD
Barnes
Nicholas M
NM
Gordon
John
J
D017209:Apoptosis / Q000187:drug effects*; D001402:B-Lymphocytes / Q000187:drug effects; D002051:Burkitt Lymphoma / Q000473:pathology*; D020013:Calcium Signaling / Q000187:drug effects; D002352:Carrier Proteins / Q000037:antagonists & inhibitors; D015283:Citalopram / Q000494:pharmacology*; D005473:Fluoxetine / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D019254:Genes, bcl-2; D016259:Genes, myc; D006801:Humans; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors; D026901:Membrane Transport Proteins; D009000:Monocytes / Q000187:drug effects; D020559:Monomeric GTP-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D054778:NM23 Nucleoside Diphosphate Kinases; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000187:drug effects*; D009419:Nerve Tissue Proteins; D009701:Nucleoside-Diphosphate Kinase; D017374:Paroxetine / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics
D002352:Carrier Proteins; D015283:Citalopram; D005473:Fluoxetine; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D020559:Monomeric GTP-Binding Proteins; D054778:NM23 Nucleoside Diphosphate Kinases; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D009701:Nucleoside-Diphosphate Kinase; D017374:Paroxetine; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D014157:Transcription Factors; C493230:SLC6A4 protein, human; C517938:NME1 protein, human