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The discovery that some selective serotonin transporter- (SSRI) and norepinephrine transporter- (NSRI) targeting antidepressants have the potential to act as anticancer agents adds greatly to their diverse pharmacological application. We report that the SSRI fluoxetine and the NSRI maprotiline are potent antiproliferative agents against human Burkitt lymphoma (BL), having little effect on normal blood cells. The results of this study show that although there is low-level expression of the norepinephrine transporter (NET) in some BL cells, NET is not involved in fluoxetine- or maprotiline-mediated cell death, as neither norepinephrine nor other NET inhibitors prevented this death. Of other NET ligands investigated for activity, only desipramine was found to have a similar effect to maprotiline and fluoxetine, suggesting the existence of a common selective structural modality for cell death and aiding in the future development of more potent analogs. In this study, we also show evidence to support previous reports that the serotonin transporter (SERT) has no involvement in antidepressant-mediated cell death, as SERT-specific ligands were unable to prevent fluoxetine or maprotiline cell death and not all SERT ligands could induce cell death. Although no target has yet been identified for the action of these compounds, the cell death elicited is potent, selective, and worthy of future investigation. [ABSTRACT FROM AUTHOR]