Oral administration of fluoxetine alters the proliferation/apoptosis balance of lymphoma cells and up-regulates T cell immunity in tumor-bearing mice

Antidepressants have a controversial role with regard to their influence on cancer and immunity. Recently, we showed that fluoxetine administration induces an enhancement of the T-cell mediated immunity in naive mice, resulting in the inhibition of tumor growth. Here we studied the effects of fluoxetine on lymphoma proliferation/apoptosis and immunity in tumor bearing-mice. We found an increase of apoptotic cells (active Caspase-3(+)) and a decrease of proliferative cells (PCNA(+)) in tumors growing in fluoxetine-treated animals. In addition, differential gene expressions of cell cycle and death markers were observed. Cyclins D3, E and B were reduced in tumors from animals treated with fluoxetine, whereas the tumor suppressor p53 and the cell cycle inhibitors p15/INK4B, p16/INK4A and p27/Kip1 were increased. Besides, the expression of the antiapoptotic factor Bcl-2 and the proapoptotic factor Bad were lower and higher respectively in these animals. These changes were accompanied by increased IFN-gamma and TNF-alpha levels as well as augmented circulating CD8(+) T lymphocytes in tumor-bearing mice treated with the antidepressant. Therefore, we propose that the up-regulation of T-cell mediated antitumor immunity may be contributing to the alterations of tumor cell proliferation and apoptosis thus resulting in the inhibition of tumor progression. (C) 2011 Elsevier B.V. All rights reserved.