title: Caspase-dependent and -independent mechanisms in apoptosis induced by hydroquinone and catechol metabolites of remoxipride in HL-60 cells.
abstract: 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.
authors.affiliation: Department of Biomedical Science, Faculty of Allied Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300, Kuala Lumpur, Malaysia.
authors.forename: S H
authors.initials: SH
authors.lastname: Inayat-Hussain
authors.forename: S M
authors.initials: SM
authors.lastname: McGuinness
authors.forename: R
authors.initials: R
authors.lastname: Johansson
authors.forename: J
authors.initials: J
authors.lastname: Lundstrom
authors.forename: D
authors.initials: D
authors.lastname: Ross
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000378:metabolism / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism / Q000502:physiology*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D053938:DNA Fragmentation / Q000187:drug effects; D004789:Enzyme Activation; D018922:HL-60 Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D006873:Hydroquinones / Q000633:toxicity*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D010718:Phosphatidylserines / Q000378:metabolism; D017330:Remoxipride / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000633:toxicity*
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D014150:Antipsychotic Agents; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D006873:Hydroquinones; D007527:Isoenzymes; C112341:NCQ 344; D010718:Phosphatidylserines; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D017330:Remoxipride; C084325:NCQ 436; D020169:Caspases