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Prepublished online as a Blood First Edition Paper on December 19, 2002; DOI 10.1182/blood-2002-07-2044.
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Blood, 15 April 2003, Vol. 101, No. 8, pp. 3212-3219
NEOPLASIA
Selective serotonin reuptake inhibitors directly signal for
apoptosis in biopsy-like Burkitt lymphoma cells
Adamantios Serafeim,
Michelle J. Holder,
Gillian Grafton,
Anita Chamba,
Mark T. Drayson,
Quang T. Luong,
Christopher M. Bunce,
Christopher D. Gregory,
Nicholas M. Barnes, and
John Gordon
From the Medical Research Council (MRC) Centre for
Immune Regulation, School of Biosciences, and Division of
Neurosciences, The Medical School, University of Birmingham,
Birmingham, United Kingdom; and the MRC Centre for
Inflammation Research, University of Edinburgh, Edinburgh, United
Kingdom.
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
citalopramact 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
andbecause of its association with AIDSincreasingly more common
Burkitt lymphoma.
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