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

• Published in: Chemico-biological interactions Vol. 128; no. 1; pp. 51 - 63
• Main Authors: Inayat-Hussain, S.H, McGuinness, S.M, Johansson, R, Lundstrom, J, Ross, D
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 15.08.2000
• Subjects: Amino Acid Chloromethyl Ketones - pharmacology; Antipsychotic Agents - metabolism; Antipsychotic Agents - toxicity; Apoptosis; Apoptosis - drug effects; Apoptosis - physiology; Caspase Inhibitors; Caspases; Caspases - metabolism; Caspases - physiology; Catechol; Cysteine Proteinase Inhibitors - pharmacology; DNA Fragmentation - drug effects; Enzyme Activation; HL-60 Cells - cytology; HL-60 Cells - drug effects; HL-60 Cells - enzymology; Humans; Hydroquinone; Hydroquinones - toxicity; Isoenzymes - antagonists & inhibitors; Isoenzymes - metabolism; Isoenzymes - physiology; Phosphatidylserines - metabolism; Remoxipride; Remoxipride - analogs & derivatives; Remoxipride - metabolism; Remoxipride - toxicity; Hydroquinone; Catechol; Remoxipride; Caspases; Apoptosis
• ISSN: 0009-2797; 1872-7786
• DOI: 10.1016/S0009-2797(00)00188-5

The hydroquinone and catechol like metabolites, NCQ344 and NCQ436 respectively, of the antipsychotic remoxipride have recently been demonstrated to induce apoptosis in myeloperoxidase (MPO)-rich human bone marrow progenitor and HL-60 cells [S.M. McGuinness, R. Johansson, J. Lundstrom, D. Ross, Induction of apoptosis by remoxipride metabolites in HL-60 and CD34+/CD19− human bone marrow progenitor cells: potential relevance to remoxipride-induced aplastic anemia, Chem. Biol. Interact. 121 (1999) 253–265]. In the present study, we determined the molecular mechanisms of apoptosis induced by these remoxipride metabolites in HL-60 cells. Our results show that apoptosis was accompanied by phosphatidylserine (PS) exposure, activation of caspases-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 activation of caspases-9, -3/-7. In addition, PS exposure was significantly but not completely inhibited by Z-VAD.FMK. These results demonstrate that although Z-VAD.FMK inhibitable caspases are necessary for maximal apoptosis induced by NCQ344 and NCQ436, additional caspase-independent processes may orchestrate changes leading to PS exposure during apoptosis induced by the remoxipride polyphenolic metabolites.