Selective serotonin reuptake inhibitors--a new modality for the treatment of lymphoma/leukaemia?

Biochem Pharmacol. 2007 Nov 1;74(9):1424-35. doi: 10.1016/j.bcp.2007.07.017. Epub 2007 Jul 20.

Abstract

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 10 microM 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 microM 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects*
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / chemically induced*
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Humans
  • Inhibitory Concentration 50
  • Leukemia, Erythroblastic, Acute* / drug therapy
  • Leukemia, Erythroblastic, Acute* / metabolism
  • Leukemia, Erythroblastic, Acute* / pathology
  • Lymphoma, B-Cell* / drug therapy
  • Lymphoma, B-Cell* / metabolism
  • Lymphoma, B-Cell* / pathology
  • Lymphoma, T-Cell* / drug therapy
  • Lymphoma, T-Cell* / metabolism
  • Lymphoma, T-Cell* / pathology
  • Mice
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Serotonin / metabolism
  • Serotonin Uptake Inhibitors / chemical synthesis
  • Serotonin Uptake Inhibitors / metabolism
  • Serotonin Uptake Inhibitors / pharmacology*
  • Serotonin Uptake Inhibitors / therapeutic use
  • Thymidine / metabolism

Substances

  • Antineoplastic Agents
  • Proto-Oncogene Proteins c-bcl-2
  • Serotonin Uptake Inhibitors
  • Serotonin
  • Thymidine