Inhibitory effect of fluoxetine on lymphoma growth through the modulation of antitumoral T cell response by serotonin dependent and independent mechanisms

FRICK LR; PALUMBO ML; ZAPPIA MP; BROCCO MA; CREMASCHI GA; GENARO AM

Buenos Aires

Congreso; XXXIX Reunión Anual de la Sociedad Argentina de Farmacología Experimental (SAFE); 2007

SAFE

Fluoxetine, a selective serotonin reuptake inhibitor, is widely used for the treatment of depressive symptoms of cancer patients, but there are contradictory evidences about its effects on immunity and neoplastic processes. Thus, we studied the effects of fluoxetine on a T-cell lymphoma growing in syngeneic mice and on antitumoral T-cell immunity. Chronic fluoxetine administration improved tumor prognosis, i.e. reduced tumor growth, and increased latency of apparition and survival. In addition, fluoxetine treatment also enhanced T cell proliferation to the selective mitogen Con A, evaluated by [3H]thymidine incorporation. It also increased the expression of the antitumoral cytokines TNF-alpha and IFN-gamma, measured by Real Time RT-PCR, without affecting CD4+ and CD8+ T lymphocyte subsets analyzed by dual fluorescence flow cytometry. In vitro, fluoxetine did not affect tumor cells proliferation, but it exerted a direct effect on T lymphocytes. Both fluoxetine and serotonin stimulated proliferation induced by a suboptimal mitogen concentration but inhibited proliferation at the optimal one. Both effects were directly related to the concentrations used for serotonin but indirectly related for fluoxetine. When both drugs were combined, the results suggested that the effects of fluoxetine are in part independent of its ability to elevate serotonin extracellular levels. These findings indicate that fluoxetine inhibits tumor growth through modulation of T-cell mediated immunity by direct serotonin-dependent and independent mechanisms.