Sci. STKE, 22 April 2003
CANCER Lymphocytes Listen to Prozac
A new study adds an unexpected wrinkle to the long-standing debate concerning the impact of emotional state on cancer, by suggesting that selective serotonin reuptake inhibitors (SSRIs), a class of antidepressant drugs, may promote apoptosis in lymphoma cells independent of their effects on depression. In Burkitt's lymphoma, a highly aggressive malignancy associated with c-myc dysregulation, the malignant cells couple a tremendous rate of proliferation with a high rate of apoptosis. Serafeim et al., who recently showed that serotonin promotes apoptosis in Burkitt's lymphoma cell lines (BL cells), now report that SSRIs also promote BL cell apoptosis, as well as affect Ca2+ handling and tyrosine phosphorylation. In early passage BL cells, chemically distinct SSRIs (fluoxetine, paroxetine, and citralopram) inhibited DNA synthesis and led to accumulation of cells in the G0 and G1 phases of the cell cycle. SSRIs reduced the number of viable cells and elicited such hallmarks of apoptosis as caspase activation, poly(ADP-ribose)polymerase-1 cleavage, collapsed mitochondrial membrane potential, and DNA fragmentation. Apoptosis was reversed by Bcl-2 overexpression. Normal B cells, peripheral blood mononuclear cells, and non-Burkitt's lymphoid cell lines were resistant to SSRI-induced death. Fluoxetine promoted tyrosine phosphorylation of various proteins and elevated intracellular Ca2+ concentration ([Ca2+]i); [Ca2+]i elevation was sensitive to treatment with thapsigargin to deplete endoplasmic reticulum Ca2+ stores and to extracellular application of the Ca2+ chelator EGTA. These data suggest a possible role for the SSRIs as a component of Burkitt's therapy.
Promotion of apoptosis is desirable in cancer therapies; however, albumin, the most abundant protein in human plasma, may sometimes inhibit this process. Jones et al. discovered that albumin activated Akt signaling and blocked the ability of gamma irradiation or the antineoplastic drug chlorambucil to induce apoptosis in chronic lymphocytic leukemia (CLL) cells. Akt activation by albumin and by human plasma was suppressed by the phosphatidylinositol 3-kinase inhibitor LY294002, which increased cell sensitivity to chlorambucil. The authors suggest that further characterization of albumin's antiapoptotic effect could lead to the development of novel therapies.
A. Serafeim, M. J. Holder, G. Grafton, A. Chamba, M. T. Drayson, Q. T. Luong, C. M. Bunce, C. D. Gregory, N. M. Barnes, J. Gordon, Selective serotonin reuptake inhibitors directly signal for apoptosis in biopsy-like Burkitt lymphoma cells. Blood 101, 3212-3219 (2003). [Online Journal]
D. T. Jones, K. Ganeshaguru, R. J. Anderson, T. R. Jackson, K. R. Bruckdorfer, S. Y. Low, L. Palmqvist, H. G. Prentice, A. V. Hoffbrand, A. B. Mehta, R. G. Wickremasinghe, Albumin activates the AKT signaling pathway and protects B-chronic lymphocytic leukemia cells from chlorambucil- and radiation-induced apoptosis. Blood 12, 3174-3180 (2003). [Online Journal]
Citation: Lymphocytes Listen to Prozac. Sci. STKE 2003, tw156 (2003).
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