Effector caspase activation, in the absence of a conspicuous apoptosis induction, in mononuclear cells treated with azidothymidine

Abstract

In the present study we focused our attention on the effect of AZT, at pharmacological and suprapharmacological concentrations, on some apoptosis-related key events and, particularly, on caspase activation in fresh human peripheral blood mononuclear cells (PBMCs). The main results can be summarized as follows: (i) AZT induced a strong, dose-dependent antiproliferative effect in mitogen-stimulated PBMCs, but low levels of cytotoxicity. in comparison with 5FU; (ii) low levels of cytotoxicity were coupled with a poor increase of apoptosis after AZT treatment in PBMCs; (iii) despite low levels of apoptosis, remarkable signs of both initiator and effector caspase enhanced expression with respect to control were detected by immunoblot analysis in AZT-treated PBMCs; (iv) enhanced caspase expression was associated with an increased expression of both anti-apoptotic Bcl-2 and pro-apoptotic Fas and p53 proteins, as detected by flow cytometry analysis; (v) combination treatment in vitro with AZT and anti-Fas significantly increased apoptosis in PBMCs with respect to single treatments. Overall, these results suggest that AZT treatment activates a complex, and apparently contrasting apoptosis-related signaling activity in PBMCs and that additional events are necessary to disrupt the balance induced by AZT towards apoptosis, on these cells.