Caspase-dependent and -independent mechanisms in apoptosis induced by hydroquinone and catechol metabolites of remoxipride in HL-60 cells

The hydroquillone and catechol like metabolites, NCQ344 and NCQ436 respecti vely, of the antipsychotic remoxipride have recently been demonstrated to i nduce apoptosis in myeloperoxidase (MPO)-rich human bone marrow progenitor and HL-60 cells [S.M. McGuinness, R. Johansson, J. Lundstrom, D. Ross, Indu ction of apoptosis by remoxipride metabolites in HL-60 and CD34 + /CD19 - h uman bone marrow progenitor cells: potential relevance to remoxipride-induc ed aplastic anemia. Chem. Biol. Interact. 121 (1999) 253-265]. In the prese nt study, we determined the molecular mechanisms of apoptosis induced by th ese remoxipride metabolites in HL-60 cells. Our results show that apoptosis was accompanied by phosphatidylserine (PS) exposure, activation of caspase s-9, -3, -7 and DNA cleavage. In HL-60 cells treated with the hydroquinone NCQ344 and catechol NCQ436, the general caspase inhibitor benzyloxycarbonyl -Val-Ala-Asp.fluoromethyl ketone (Z-VAD.FMK) blocked DNA cleavage and activ ation of caspases-9, -3/-7. In addition, PS exposure was significantly but not completely inhibited by Z-VAD.FMK. These results demonstrate that altho ugh Z-VAD.FMK inhibitable caspases are necessary for maximal apoptosis indu ced by NCQ344 and NCQ436, additional caspase-independent processes may orch estrate changes leading to PS exposure during apoptosis induced by the remo xipride polyphenolic metabolites. (C) 2000 Elsevier Science Ireland Ltd. Al l rights reserved.