Emoxipine Modulates Concentration-Dependent Effects of Cytarabine and Cyclocytidine on Activation of Human T Cells

Abstract

Title: Emoxipine modulates concentration-dependent effects of cytarabine and cyclocytidine on activation of human T cells. Introduction: Both cytarabine and cyclocytidine are used in the treatment of acute myeloid leukemia. Well known that cytarabine and other related cytosine-based nucleoside analogues are being toxic to tumor cells by increasing levels of cellular oxidative stress as it could be abrogated by antioxidants. However, very little is known both about both the effects of combinations of antimetabolites with antioxidants on the cytotoxic innate and adaptive immune cells and whether lymphocytes toxicity affects its anticancer efficiency. Aim: To estimate effects of cytarabine and cyclocytidine with emoxipine on in vitro activated human T cells at concentrations reached during in vivo treatment with high doses, conventional doses and low doses. Materials and Methods: T cells derived from blood donors were activated in vitro in cell culture medium alone or supplemented with cytarabine 0.1-10.0 μM or cyclocytidine 0.1-10.0 μM. Cell characteristics were assessed by flow cytometry. Results: Only cytarabine 1.0-10.0 μM had both antiproliferative and proapoptotic effects. Additionally, these cytarabine concentrations increased the γIFN-producing by CD3+CD4+ T cells and did not affect the release of this cytokine by CD3+CD8+ T cells. In contrast, the lowest concentration (0.1 μM) did not have or showed minor antiproliferative or cytotoxic effects, did not alter the release of γIFN. Cyclocytidine did not affect viability of normal peripheral blood mononuclear cells but decreased the proliferative capacity of activated normal T cells in dose-dependent manner. Additionally, cyclocytidine  altered the percentage of γIFN-producing proliferative CD3+CD8+ cytotoxic T cells for any concentration tested (0.1, 1.0, 1 and 10.0 μM) meanwhile highly suppressed the number of the whole amount of CD3+CD8+ cells and did not affect the release of cytokines by CD3+CD4+ T cells. The study of the expression of the CD107a marker showed a significant stimulating effect of 10 µm of citarabine on the activation of subpopulations of T-lymphocytes (CD3+) and cytotoxic T-lymphocytes (CD3+CD8+).